Synthesis of quinoxaline analogues

Article abstract of DOI:10.1055/s-0030-1260147

Substituted tricyclic or tetracyclic quinoxalines, tricyclic pyridoquinoxalines and bis-quinoxalines were synthesized in high yields starting from cyclic ketones by the -bromination of cyclic ketones with N-bromosuccinimide (NBS) followed by condensation of the resulting -bromo ketones with 1,2-diaminobenzene, 3,4-diaminopyridine, or 3,3-diaminobenzidine. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0030-1260147

PAPER
3143
Synthesis of Quinoxaline Analogues
S
ynthesis of
Q
uinoxali
e
ne
A
nalogu
n
e
s
g-Yang Chang,*a Tein-Wei Lee,a Ru-Ting Hsu,b Tzu-Lin Yenc
a
b
c
Department of Nursing, ShuZen College of Medicine and Management, Luju, Kaohsiung 821, Taiwan
Department of Nursing, Kaohsiung Municipal Hsiao-Kang Hospital, Kaohsiung Medical University, Kaohsiung 807, Taiwan
Received 31 May 2011; revised 3 July 2011
addition sequence was achieved from the reaction of cy-
clohexanone (1a; 1.0 mmol) with NBS (1.05 mmol) in
acetic acid (5 mL), followed by the addition of the result-
ing a-bromo ketone with 1,2-diaminobenzene (1.1
Abstract: Substituted tricyclic or tetracyclic quinoxalines, tricyclic
pyridoquinoxalines and bis-quinoxalines were synthesized in high
yields starting from cyclic ketones by the a-bromination of cyclic
ketones with N-bromosuccinimide (NBS) followed by condensa-
tion of the resulting a-bromo ketones with 1,2-diaminobenzene, mmol), as shown in Scheme 1. The major difference be-
3,4-diaminopyridine, or 3,3¢-diaminobenzidine.
tween the construction of the two frameworks of benzodi-
azepine 2 and quinoxaline 3a8b is the sequence of addition
of the reagents [NBS, cyclohexanone (1a), then 1,2-di-
aminobenzene].
Key words: condensation, halogenation, tandem reactions, hetero-
cycles, arenes
Quinoxaline heterocycles are important benzoheterocy-
cles in combinatorial drug discovery libraries.1 There are
a number of processes available to generate the structural
skeleton of quinoxalines, but they are generally synthe-
sized by the condensation of 1,2-dicarbonyls with 1,2-di-
amines in either acetic acid or ethanol heated to reflux.2
Some recent reactions of 1,2-diaminobenzene with a-di-
carbonyl equivalents are described as follows: (1) ep-
oxides in the presence of Bi(0) and acid derivatives,3 (2)
ketones and potassium hydroxide in PEG 400,4 (3) a-bro-
mo ketones in an aqueous media system5 or by use of solid
phase chemistry,6 (4) hydroxylimino ketones under mi-
crowave irradiation,7 (5) a-hydroxyketones8 by the use of
iodine,9 sulfamic acid,10 nanoparticles,11 metal complex-
mediated tandem oxidation process,12 and other notable
approaches.13 Although a great number of quinoxalines
and their derivatives with this specific substitution pattern
have been developed, new methods for their preparation
are needed. Since the above-mentioned procedures are al-
most all multi-step reactions, we wanted to explore a one-
pot methodology14 for the preparation of tricyclic or tetra-
cyclic quinoxaline skeletons by the a-bromination of cy-
clic ketones with N-bromosuccinimide (NBS) in acetic
acid, followed by the addition of different aryl-1,2-di-
amines (e.g., 1,2-diaminobenzene; 3,4-diaminopyridine
or 3,3¢-diaminobenzidine).
H
N
NBS, 1,2-(NH2)2C6H4
O
solvent-free conditions
N
2
O
N
NBS
then
Br
1a
N
AcOH
1,2-(NH2)2C6H4
3a
Scheme 1 NBS-mediated synthetic strategies toward benzodiaze-
pine 2 and quinoxaline 3a from ketone 1a. For benzodiazepine 2: 1
(4.0 mmol), NBS (10%), 1,2-diaminobenzene (1.0 mmol). For
quinoxaline 3a: 1 (1.0 mmol), NBS (1.05 mmol), 1,2-diaminobenzene
(1.1 mmol).
In previous studies, we have explored the synthetic appli-
cation of N-benzenesulfonyl-3-bromopiperidin-4-one (4)
to generate the structural framework of 4,4-dialkoxy-3-pi-
peridinol
5 with a range of sodium alkoxides
(Scheme 2).16 Furthermore, treatment of compound 4
RO
O
OR
OH
N
NaOR, THF
(ref. 16)
O
O
S
5
O
Br
Recently, Yao et al. reported that NBS (10 mol%) promot-
ed the synthesis of 1,5-benzodiazepine 2 through the reac-
tion of cyclohexanone (1a; 4.0 mmol) with 1,2-
diaminobenzene (1.0 mmol) either at r.t. or at 40 °C under
solvent-free conditions.15 Three components were added
almost simultaneously for the one-pot reaction. However,
our concise synthesis of quinoxaline 3a with the ordinal
Ph
NBS, AcOH
(82%)
N
N
S
S
1,2-(NH2)2C6H4
AcOH (61%)
O
O
O
O
Ph
Ph
N
N
1b
4
N
S
3b
SYNTHESIS 2011, No. 19, pp 3143–3151
Advanced online publication: 01.08.2011
x
x.
x
x
.
2
0
1
1
O
O
Ph
DOI: 10.1055/s-0030-1260147; Art ID: H56511SS
© Georg Thieme Verlag Stuttgart · New York
Scheme 2 Synthetic application of a-bromopiperidin-4-one 4

3144
M.-Y. Chang et al.
PAPER
Table 1 Synthesis of Substituted Quinoxaline Analoguesa
(continued)
with 1,2-diaminobenzene in acetic acid gave compound
3b in 61% yield. The total yield of the two-step protocol
was 50%. Because acetic acid was used as the solvent in
both the bromination and condensation, the combination
of the two reactions was worthy of further study. Initially,
compound 1b (1.0 mmol) was chosen as the starting ma-
terial for the one-pot tandem reaction of quinoxaline with
NBS (1.05 equiv) and 1,2-diaminobenzene (1.1 equiv), as
shown in Table 1.
O
N
N
NBS, AcOH, then
X
n
n
X
H2N
1a–o
NH2
3a–o
Table 1 Synthesis of Substituted Quinoxaline Analoguesa
n = 0, 1, 2, 3, 7
X = NSO2Ph, NSO2Tol, O, CHMe, CHEt
Entry
5
Reactant
Product
Yield (%)
O
N
O
N
NBS, AcOH, then
N
70
N
X
n
n
X
H2N
O
1a–o
NH2
3a–o
O
1e
3e
n = 0, 1, 2, 3, 7
X = NSO2Ph, NSO2Tol, O, CHMe, CHEt
O
Entry
Reactant
Product
Yield (%)
N
6
7
52
79
N
O
1f
N
3f
1
74
N
O
1a
N
3a
N
O
1g
N
3g
N
2
72
66
67
N
S
O
N
S
N
8
O
O
O
O
8
80
N
Ph
O
O
O
O
Ph
1b
3b
1h
3h
O
N
O
N
N
3
N
S
N
9
92
N
S
O
12
Me
O
1i
Me
1c
3c
3i
O
O
N
N
N
N
10
66
4
N
S
N
S
O
1j
Tol
O
3j
Tol
1d
3d
Synthesis 2011, No. 19, 3143–3151 © Thieme Stuttgart · New York

PAPER
Synthesis of Quinoxaline Analogues
3145
Table 1 Synthesis of Substituted Quinoxaline Analoguesa
(continued)
the convenient, one-pot reaction. Furthermore, we were
able to present an atom-economic, green procedure. Since
replacing NBS with either NCS or NIS did not improve
the yields, further studies were conducted only with NBS.
In order to evaluate the effect of the solvent on the reac-
tion, a range of solvents, such as methanol, acetonitrile,
and dichloromethane, were examined. Among the differ-
ent solvents, acetic acid proved to be the best medium for
this reaction. Next, a one-pot reaction of cyclic ketones
1a–o (N-sulfonyl-piperidin-4-ones, tetrahydropyran-4-
one, cycloalkanones, and benzocycloalkanones) with
NBS and 1,2-diaminobenzene provided compounds 3a–o.
The total synthetic procedure could be monitored by TLC
until the reaction was complete (within 8 h).
O
N
N
NBS, AcOH, then
X
n
n
X
H2N
1a–o
NH2
3a–o
n = 0, 1, 2, 3, 7
X = NSO2Ph, NSO2Tol, O, CHMe, CHEt
Entry
11
Reactant
Product
Yield (%)
According to the procedure, the skeleton of quinoxaline
with a range of functional groups was also synthesized in
moderate yields. Eleven tricyclic quinoxaline analogues
3a–k (52–92% yields) and four tetracyclic quinoxaline
analogues 3l–o (60–82% yields) were generated. In com-
parison to the isolated yields of quinoxaline products with
different ring sizes, it was found that the larger-ring com-
pounds were more suitable. Attempts to extend this reac-
tion to cyclobutanone were unsuccessful. A possible
reason might be that ring strain was a key factor affecting
the distribution of yields. In Table 1, entries 13 and 14,
when the benzocyclohexanone skeleton was chosen as the
reactant, benzo[a]phenazines 3m and 3n were isolated by
using the in situ aromatization procedure. The skeleton of
b-lapachone benzo[a]phenazine has attracted consider-
able attention because of its interesting biological activi-
ties,17 including anti-malarial18 and anti-hepatitis C viral
replication properties.19 The structural frameworks of
compounds 3b, 3h, 3m, and 3o were determined by using
single-crystal X-ray analysis (Figure 1 and Figure 2).20
O
N
N
62
1k
3k
O
N
12
13
60
79
N
1l
3l
O
N
N
1m
3m
With these results in hand, other aromatic diamines were
further investigated. The reaction of ketone 1a, 1i or 1j
with NBS (1.05 equiv) and 3,4-diaminopyridine (1.1
equiv) was examined, as shown in Table 2. The pyri-
doquinoxaline analogues 6a–c were also afforded in 66–
90% yields. For Table 2, entry 3, product 6c was generat-
ed as an isomeric mixture with a ratio of nearly 1:1. We
then further expanded the scope of the double-condensa-
tion strategy to the skeleton of bis-quinoxaline through the
use of 3,3¢-diaminobenzidine instead of 1,2-diaminoben-
zene or 3,4-diaminopyridine. Three bis-quinoxaline ana-
logues 7a–c, with a five-, seven-, and six-membered ring,
respectively, were afforded in 43–80% yields by treat-
ment of compounds 1f, 1g or 1k (1.0 mmol) with NBS
(1.05 equiv) and 3,3¢-diaminobenzidine (0.5 equiv). This
present methodology is the simplest and perhaps quickest
synthesis of quinoxaline, pyridoquinoxaline, and bis-
quinoxaline derivatives available.
O
N
N
14
15
80
82
1n
1o
3n
3o
O
N
N
a The products were >95% pure as judged by 1H NMR analysis.
The synthetic strategy was first applied to the synthesis of
a series of tricyclic or tetracyclic quinoxaline analogues.
Cyclic ketones, in particular, were examined because few-
er tricyclic quinoxalines have been reported.4,13 Under the
above conditions, compound 3b was obtained in 72%
yield. The elevated yields should be a major advantage of
To increase the synthetic potential, an acyclic ketone was
also submitted to the facile one-pot methodology. Thus, 2-
phenylquinoxaline was provided in 87% yield via treat-
ment of acetophenone with NBS followed by addition of
1,2-diaminobenzene under the conditions described
above.
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M.-Y. Chang et al.
PAPER
Table 2 Synthesis of Quinoxaline Analogues 6 and 7a
N
N
H2N
N
X
NH2
N
(for 1a, 1i, 1j)
(for 1f, 1g, 1k)
O
6a–c
n
NBS, AcOH
then
n
X
1
N
X
N
N
N
H2N
NH2
NH2
NH2
n
7a–c
X
n
Entry
1
Reactant
Product
Yield (%)
66
N
O
N
N
1a
6a
N
O
N
N
2
90
12
1i
6b
N
N
N
+
O
N
N
3
N
70
1j
6c
O
N
N
4
5
43
80
N
N
1f
7a
O
N
N
N
N
1g
7b
7c
O
N
N
6
78
N
N
1k
a The isolated products were >95% pure as judged by 1H NMR analysis.
Synthesis 2011, No. 19, 3143–3151 © Thieme Stuttgart · New York

PAPER
Synthesis of Quinoxaline Analogues
3147
ed in parts per million (ppm) and the coupling constants (J) are giv-
en in hertz. High-resolution mass spectra (HRMS) were measured
with a Finnigan/Thermo Quest MAT 95XL mass spectrometer. X-
ray crystal structures were obtained with an Enraf-Nonius FR-590
diffractometer (CAD4, Kappa CCD). Elemental analyses were car-
ried out with Heraeus Vario III-NCSH, Heraeus CHN-OS-Rapid
Analyzer or Elementar Vario EL III instruments.
Synthesis of Skeleton 3; General Procedure
NBS (94 mg, 0.53 mmol) was added to a stirred solution of 1a–o
(0.5 mmol) in AcOH (5 mL) at r.t. and the reaction mixture was
stirred at reflux for 2–4 h and then cooled to r.t.. 1,2-Diaminoben-
zene (59 mg, 0.55 mmol) was added at r.t. and the reaction mixture
was further stirred at reflux for 2–4 h and then again cooled to r.t.
CH2Cl2 (20 mL) and sat. aq NaHCO3 (10 mL) were added to the re-
action mixture, which was cooled in an ice bath. The residue was
extracted with CH2Cl2 (3 × 20 mL) and the combined organic layers
were washed with brine (3 × 10 mL), dried, filtered and evaporated
to afford the crude product. Purification on silica gel (hexanes–
EtOAc, 4:1→1:1) afforded compounds 3a–o.
Figure 1 X-ray crystal structures of compounds 3b and 3h
1,2,3,4-Tetrahydrophenazine (3a)
Compound 3a is a known compound and the analytical data are con-
sistent with those reported in the literature.8b
Yield: 68 mg (74%); mp 92–93 °C (recrystallized from hexanes and
EtOAc); Rf = 0.2 (hexanes–EtOAc, 2:1).
IR (CHCl3): 3008, 2937, 1578, 1459, 1423, 1384, 1330, 1291, 1238
cm–1.
1H NMR (400 MHz): d = 7.98–7.96 (m, 2 H), 7.62–7.56 (m, 2 H),
3.19–3.17 (br s, 4 H), 2.06–2.03 (br s, 4 H).
13C NMR (100 MHz): d = 154.19 (2×), 141.20 (2×), 128.95 (2×),
128.28 (2×), 33.32 (2×), 22.79 (2×).
HRMS (ESI): m/z [M + 1]+ calcd for C12H13N2: 185.1079; found:
185.1081.
Anal. Calcd for C12H12N2: C, 78.23; H, 6.57; N, 15.21. Found: C,
78.49; H, 6.86; N, 15.42.
2-Benzenesulfonyl-1,2,3,4-tetrahydropyrido[3,4-b]quinoxaline
(3b)
Yield: 117 mg (72%); mp 179–180 °C (recrystallized from hexanes
and EtOAc); Rf = 0.2 (hexanes–EtOAc, 1:1).
IR (CHCl3): 2957, 1559, 1491, 1449, 1368 cm–1.
Figure 2 X-ray crystal structure of compound 3o
1H NMR (400 MHz): d = 7.96–7.93 (m, 2 H), 7.80–7.76 (m, 2 H),
7.71–7.68 (m, 2 H), 7.63–7.51 (m, 3 H), 4.54 (s, 2 H), 3.60 (t,
J = 6.0 Hz, 2 H), 2.51 (t, J = 6.0 Hz, 2 H).
13C NMR (100 MHz): d = 149.74, 147.88, 141.43, 140.96, 134.15,
133.11, 129.96, 129.77, 129.26 (2×), 128.46, 128.45, 127.39 (2×),
45.76, 43.71, 32.19.
In summary, a straightforward, one-pot, concise synthesis
of the polycyclic quinoxaline analogues 3a–o, 6a–c, and
7a–c from treatment of cyclic ketones 1a–o with NBS in
acetic acid followed by condensation by addition of 1,2-
diaminobenzene, 3,4-diaminopyridine or 3,3¢-diamino-
benzidine has been developed. Further investigation is re-
quired to establish the structure–activity relationships of
the polycyclic quinoxaline analogues.
HRMS (ESI): m/z [M + 1]+ calcd for C17H16N3O2S: 326.0963;
found: 326.0966.
Anal. Calcd for C17H15N3O2S: C, 62.75; H, 4.65; N, 12.91. Found:
C, 63.02; H, 4.90; N, 13.10.
THF was distilled prior to use. All other reagents and solvents were
obtained from commercial sources and used without further purifi-
cation. Reactions were routinely carried out under an atmosphere of
dry nitrogen with magnetic stirring. Products in organic solvents
were dried with anhydrous magnesium sulfate before concentration
in vacuo. Melting points were determined with an SMP3 melting-
point apparatus. Infrared spectra were recorded with a Perkin–Elmer
Single-Crystal X-ray Structure of 3b
Grown by slow diffusion of EtOAc into a solution of compound 3b
in CH2Cl2 to yield a colorless prism. The compound crystallizes in
the triclinic crystal system; space group P1; a = 6.7112(2) Å,
b = 10.0918(2) Å, c = 11.1626(3) Å; V = 720.59(3) Å3; Z = 2;
dcalcd = 1.389 g/cm3; F(000) = 320, 2q range 1.85–26.38°, R indices
(all data) R1 = 0.0539, wR2 = 0.1470.
1
100 series FTIR spectrometer. H and 13C NMR spectra were re-
corded with a Varian INOVA-400 spectrometer operating at 200/
400 and at 50/100 MHz, respectively. Chemical shifts (d) are report-
Synthesis 2011, No. 19, 3143–3151 © Thieme Stuttgart · New York

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M.-Y. Chang et al.
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2-Methanesulfonyl-1,2,3,4-tetrahydropyrido[3,4-b]quinoxaline
(3c)
Yield: 87 mg (66%); mp 166–167 °C (recrystallized from hexanes
and EtOAc); Rf = 0.2 (hexanes–EtOAc, 1:1).
IR (CHCl3): 2951, 1612, 1439, 1355 cm–1.
1H NMR (400 MHz): d = 7.96–7.92 (m, 2 H), 7.64–7.60 (m, 2 H),
3.19–3.16 (m, 4 H), 1.94–1.88 (m, 2 H), 1.82–1.77 (m, 4 H).
13C NMR (100 MHz): d = 158.84 (2×), 140.61 (2×), 128.79 (2×),
IR (CHCl3): 2955, 1548, 1482, 1440, 1361 cm–1.
128.27 (2×), 38.70 (2×), 31.89, 26.82 (2×).
1H NMR (400 MHz): d = 7.96–7.93 (m, 2 H), 7.80–7.76 (m, 2 H),
4.50 (s, 2 H), 3.52 (t, J = 6.0 Hz, 2 H), 2.78 (s, 3 H), 2.26 (t,
J = 6.0 Hz, 2 H).
13C NMR (100 MHz): d = 149.96, 146.87, 142.08, 141.19, 129.53,
129.47, 128.09, 128.07, 46.11, 44.07, 34.46, 30.01.
HRMS (ESI): m/z [M + 1]+ calcd for C13H15N2: 199.1235; found:
199.1234.
Anal. Calcd for C13H14N2: C, 78.75; H, 7.12; N, 14.13. Found: C,
78.97; H, 7.45; N, 14.25.
HRMS (ESI): m/z [M + 1]+ calcd for C12H14N3O2S: 264.0807;
found: 264.0808.
6,7,8,9,10,11-Hexahydro-cycloocta[b]quinoxaline (3h)
Compound 3a is a known compound and the analytical data are con-
sistent with those reported in the literature.4a,b
Anal. Calcd for C12H13N3O2S: C, 54.74; H, 4.98; N, 15.96. Found:
C, 54.96; H, 5.23; N, 16.08.
Yield: 85 mg (80%); mp 118–119 °C (recrystallized from hexanes
and EtOAc); Rf = 0.2 (hexanes–EtOAc, 4:1).
2-(4-Methylphenyl)sulfonyl-1,2,3,4-tetrahydropyrido[3,4-
b]quinoxaline (3d)
Yield: 114 mg (67%); mp 189–190 °C (recrystallized from hexanes
and EtOAc); Rf = 0.2 (hexanes–EtOAc, 1:1).
IR (CHCl3): 2954, 1638, 1436, 1332 cm–1.
1H NMR (400 MHz): d = 8.01–7.97 (m, 2 H), 7.67–7.63 (m, 2 H),
3.20–3.17 (m, 4 H), 1.93–1.87 (m, 4 H), 1.45–1.40 (m, 4 H).
13C NMR (100 MHz): d = 157.74 (2×), 141.36 (2×), 128.77 (2×),
128.41 (2×), 34.94 (2×), 30.91 (2×), 26.02 (2×).
HRMS (ESI): m/z [M + 1]+ calcd for C14H17N2: 213.1392; found:
213.1394.
IR (CHCl3): 2963, 1555, 1444, 1339 cm–1.
1H NMR (400 MHz): d = 7.99–7.93 (m, 2 H), 7.77–7.65 (m, 4 H),
7.33–7.29 (m, 2 H), 4.52 (s, 2 H), 3.58 (t, J = 6.0 Hz, 2 H), 2.40 (s,
3 H), 2.21 (t, J = 6.0 Hz, 2 H).
13C NMR (100 MHz): d = 149.80, 148.00, 144.17, 141.40, 140.96,
129.93, 129.86 (2×), 129.76, 129.00, 128.45 (2×), 128.41, 127.75,
50.56, 43.71, 32.19, 21.47.
HRMS (ESI): m/z [M + 1]+ calcd for C18H18N3O2S: 340.1120;
found: 340.1122.
Anal. Calcd for C14H16N2: C, 79.21; H, 7.60; N, 13.20. Found: C,
79.45; H, 7.93; N, 13.41.
Single-Crystal X-ray Structure of 3h
Grown by slow diffusion of EtOAc into a solution of compound 3h
in CH2Cl2 to yield a prism. The compound crystallizes in the orthor-
hombic crystal system; space group P212121; a = 8.842(5) Å,
b = 10.429(5) Å, c = 12.574(6) Å; V = 1159.6(10) Å3; Z = 4;
dcalcd = 1.216 g/cm3; F(000) = 456, 2q range 3.24–26.49°, R indices
(all data) R1 = 0.1096, wR2 = 0.1181.
Anal. Calcd for C18H17N3O2S: C, 63.70; H, 5.05; N, 12.38. Found:
C, 63.92; H, 5.25; N, 12.49.
3,4-Dihydro-1H-pyrano[3,4-b]quinoxaline (3e)
Yield: 65 mg (70%); mp 88–89 °C (recrystallized from hexanes and
EtOAc); Rf = 0.3 (hexanes–EtOAc, 2:1).
IR (CHCl3): 2945, 1610, 1422, 1341 cm–1.
1H NMR (400 MHz): d = 8.02–7.97 (m, 2 H), 7.74–7.69 (m, 2 H),
5.01 (s, 2 H), 4.21 (t, J = 6.0 Hz, 2 H), 3.29 (t, J = 6.0 Hz, 2 H).
13C NMR (100 MHz): d = 151.24, 150.52, 141.68, 141.16, 129.55,
129.49, 128.60, 128.58, 70.31, 65.61, 32.43.
HRMS (ESI): m/z [M + 1]+ calcd for C11H11N2O: 187.0871; found:
187.0871.
6,7,8,9,10,11,12,13,14,15-Decahydro-5,16-diaza-cyclodode-
ca[b]naphthalene (3i)
Yield: 123 mg (92%); mp 81–82 °C (recrystallized from hexanes
and EtOAc); Rf = 0.2 (hexanes–EtOAc, 4:1).
IR (CHCl3): 2934, 1641, 1429, 1333 cm–1.
1H NMR (400 MHz): d = 7.98–7.96 (m, 2 H), 7.65–7.63 (m, 2 H),
3.05 (t, J = 7.6 Hz, 4 H), 1.98–1.92 (m, 4 H), 1.54–1.38 (m, 12 H).
13C NMR (100 MHz): d = 157.28 (2×), 140.96 (2×), 128.77 (2×),
128.33 (2×), 32.44 (2×), 27.95 (2×), 26.39 (2×), 25.48 (2×), 23.06
(2×).
Anal. Calcd for C11H10N2: C, 70.95; H, 5.41; N, 15.04. Found: C,
71.30; H, 5.72; N, 14.89.
HRMS (ESI): m/z [M + 1]+ calcd for C18H25N2: 269.2018; found:
269.2019.
2,3-Dihydro-1H-cyclopenta[b]quinoxaline (3f)
Yield: 44 mg (52%); mp 93–94 °C (recrystallized from hexanes and
EtOAc); Rf = 0.2 (hexanes–EtOAc, 4:1).
Anal. Calcd for C18H24N2: C, 80.55; H, 9.01; N, 10.44. Found: C,
80.77; H, 9.32; N, 10.76.
IR (CHCl3): 2948, 1633, 1432, 1349 cm–1.
1H NMR (400 MHz): d = 8.01–7.97 (m, 2 H), 7.67–7.63 (m, 2 H),
3.19 (t, J = 7.6 Hz, 4 H), 2.29 (quint., J = 7.6 Hz, 2 H).
2-Methyl-1,2,3,4-tetrahydrophenazine (3j)
Yield: 65 mg (66%); oil; Rf = 0.2 (hexanes–EtOAc, 4:1).
IR (CHCl3): 2937, 1618, 1449, 1312 cm–1.
1H NMR (400 MHz): d = 7.97–7.92 (m, 2 H), 7.65–7.61 (m, 2 H),
3.26–3.20 (m, 2 H), 3.10 (ddd, J = 6.0, 11.6, 17.6 Hz, 1 H), 2.73
(dd, J = 10.8, 17.6 Hz, 1 H), 2.18–2.06 (m, 2 H), 1.70–1.58 (m,
1 H), 1.16 (d, J = 6.4 Hz, 3 H).
13C NMR (100 MHz): d = 160.54 (2×), 141.49 (2×), 128.71 (2×),
128.68 (2×), 32.34 (2×), 21.24.
HRMS (ESI): m/z [M + 1]+ calcd for C11H11N2: 171.0922; found:
171.0924.
13C NMR (100 MHz): d = 155.74, 153.68, 141.13, 141.10, 128.76,
128.84, 128.30, 128.26, 41.49, 32.31, 30.78, 29.13, 21.52.
Anal. Calcd for C11H10N2: C, 77.62; H, 5.92; N, 16.46. Found: C,
77.46; H, 6.12; N, 16.80.
HRMS (ESI): m/z [M + 1]+ calcd for C13H15N2: 199.1235; found:
199.1233.
7,8,9,10-Tetrahydro-6H-cyclohepta[b]quinoxaline (3g)
Yield: 78 mg (79%); mp 74–75 °C (recrystallized from hexanes and
EtOAc); Rf = 0.2 (hexanes–EtOAc, 4:1).
Synthesis 2011, No. 19, 3143–3151 © Thieme Stuttgart · New York

PAPER
Synthesis of Quinoxaline Analogues
3149
Anal. Calcd for C13H14N2: C, 78.75; H, 7.12; N, 14.13. Found: C,
78.95; H, 7.39; N, 14.42.
1H NMR (400 MHz): d = 9.44–9.40 (m, 1 H), 8.33–8.29 (m, 1 H),
8.24–8.21 (m, 1 H), 8.02–7.98 (m, 1 H), 7.84–7.76 (m, 5 H), 2.76
(s, 3 H).
2-Ethyl-1,2,3,4-tetrahydrophenazine (3k)
Yield: 66 mg (62%); oil; Rf = 0.2 (hexanes–EtOAc, 4:1).
IR (CHCl3): 2926, 1635, 1432, 1351 cm–1.
13C NMR (100 MHz): d = 143.54, 142.80, 142.32, 141.64, 140.02,
133.54, 130.93, 129.79, 129.71, 129.65, 129.28, 128.98, 127.59,
126.40, 125.58, 124.46, 20.28.
1H NMR (400 MHz): d = 7.91–7.86 (m, 2 H), 7.59–7.54 (m, 2 H),
3.13 (ddt, J = 2.0, 4.8, 17.6 Hz, 2 H), 3.01 (ddt, J = 6.4, 11.6,
17.6 Hz, 1 H), 2.66 (dd, J = 11.2, 17.6 Hz, 1 H), 2.11–2.04 (m,
1 H), 1.84–1.75 (m, 1 H), 1.59–1.49 (m, 1 H), 1.46–1.37 (m, 2 H),
0.96 (t, J = 7.6 Hz, 3 H).
HRMS (ESI): m/z [M + 1]+ calcd for C17H13N2: 245.1083; found:
245.1084.
Anal. Calcd for C17H12N2: C, 83.58; H, 4.95; N, 11.47. Found: C,
83.82; H, 5.12; N, 11.62.
13C NMR (100 MHz): d = 153.81, 153.66, 140.96, 140.94, 128.72,
128.70, 128.13, 128.11, 39.19, 35.60, 32.18, 28.66, 28.37, 11.29.
6,7-Dihydro-5H-8,13-diazabenzo[3,4]cyclohepta[1,2-b]naph-
thalene (3o)
Yield: 101 mg (82%); mp 92–93 °C (recrystallized from hexanes
and EtOAc); Rf = 0.2 (hexanes–EtOAc, 2:1).
IR (CHCl3): 3023, 1376, 1107 cm–1.
1H NMR (400 MHz): d = 8.18–8.14 (m, 1 H), 8.11–8.07 (m, 1 H),
7.86–7.84 (m, 1 H), 7.73–7.69 (m, 2 H), 7.47–7.40 (m, 2 H), 7.29–
7.27 (m, 1 H), 2.96 (t, J = 7.2 Hz, 2 H), 2.64 (t, J = 7.2 Hz, 2 H),
2.41–2.34 (m, 2 H).
13C NMR (100 MHz): d = 155.62, 154.95, 141.74, 141.18, 139.11,
138.11, 129.89, 129.28, 129.22, 128.99 (2x), 128.59, 128.36,
127.08, 33.80, 30.77, 30.51.
HRMS (ESI): m/z [M + 1]+ calcd for C14H17N2: 213.1392; found:
213.1394.
Anal. Calcd for C14H16N2: C, 79.21; H, 7.60; N, 13.20. Found: C,
79.42; H, 7.81; N, 13.42.
11H-Indeno[1,2-b]quinoxaline (3l)
Yield: 65 mg (60%); mp 131–132 °C (recrystallized from hexanes
and EtOAc); Rf = 0.2 (hexanes–EtOAc, 4:1).
IR (CHCl3): 2980, 1520, 1420, 1329, 1231 cm–1.
1H NMR (400 MHz): d = 8.25–8.23 (m, 1 H), 8.17–8.14 (m, 1 H),
8.10–8.06 (m, 1 H), 7.76–7.69 (m, 2 H), 7.66–7.63 (m, 1 H), 7.57–
7.49 (m, 2 H), 4.13 (s, 2 H).
HRMS (ESI): m/z [M + 1]+ calcd for C17H15N2: 247.1235; found:
247.1236.
13C NMR (100 MHz): d = 159.42, 154.59, 143.46, 141.98, 141.17,
137.95, 131.11, 129.22, 129.14, 128.90, 128.79, 128.01, 125.77,
122.65, 35.90.
Anal. Calcd for C17H14N2: C, 82.90; H, 5.73; N, 11.37. Found: C,
83.12; H, 5.98; N, 11.55.
Single-Crystal X-ray Structure of 3o
HRMS (ESI): m/z [M + 1]+ calcd for C15H11N2: 219.0822; found:
Grown by slow diffusion of EtOAc into a solution of compound 3o
in CH2Cl2 to yield a prism. The compound crystallizes in the mon-
oclinic crystal system; space group C12/c1; a = 11.5698(3) Å,
b = 12.8032(4) Å, c = 18.2009(5) Å; V = 2573.69(13) Å3; Z = 8;
dcalcd = 1.271 g/cm3; F(000) = 1040, 2q range 2.34–26.39°, R indi-
ces (all data) R1 = 0.0718, wR2 = 0.1731.
219.0823.
Anal. Calcd for C15H10N2: C, 82.55; H, 4.62; N, 12.84. Found: C,
82.68; H, 4.87; N, 13.02.
Benzo[a]phenazine (3m)
Yield: 91 mg (79%); mp 144–145 °C (recrystallized from hexanes
and EtOAc); Rf = 0.3 (hexanes–EtOAc, 2:1).
IR (CHCl3): 3043, 1354, 1024, 767 cm–1.
1H NMR (400 MHz): d = 9.32–9.29 (m, 1 H), 8.28 (ddt, J = 0.5, 3.2,
10.0 Hz, 1 H), 8.22 (ddt, J = 0.5, 3.2, 10.0 Hz, 1 H), 7.91 (d,
J = 9.2 Hz, 1 H), 7.87 (d, J = 9.2 Hz, 1 H), 7.82–7.78 (m, 3 H),
7.75–7.67 (m, 2 H).
13C NMR (100 MHz): d = 143.37, 142.47, 142.40, 141.75, 133.12,
133.02, 130.90, 129.87, 129.66, 129.62, 129.57, 128.97, 128.01,
127.75, 126.93, 125.20.
Synthesis of Skeleton 6; General Procedure
NBS (94 mg, 0.53 mmol) was added to a stirred solution of com-
pound 1a, 1i, or 1j (0.5 mmol) in AcOH (5 mL) at r.t., and the reac-
tion mixture was stirred at reflux for 2–4 h and then cooled to r.t.
3,4-Diaminopyridine (60 mg, 0.55 mmol) was added at r.t. and the
reaction mixture was further stirred at reflux for 2–4 h and then
cooled to r.t. again. CH2Cl2 (20 mL) and sat. aq NaHCO3 (10 mL)
were added to the reaction mixture, which was cooled in an ice bath.
The residue was extracted with CH2Cl2 (3 × 20 mL) and the com-
bined organic layers were washed with brine (3 × 10 mL), dried, fil-
tered, and evaporated to afford the crude product. Purification on
silica gel (hexanes–EtOAc,2:1→1:2) afforded compounds 6a–c.
HRMS (ESI): m/z [M + 1]+ calcd for C16H11N2: 231.0922; found:
231.0923.
Anal. Calcd for C16H10N2: C, 83.46; H, 4.38; N, 12.17. Found: C,
83.80; H, 4.67; N, 12.42.
6,7,8,9-Tetrahydropyrido[3,4-b]quinoxaline (6a)
Yield: 61 mg (66%); mp 79–80 °C (recrystallized from hexanes and
EtOAc); Rf = 0.2 (hexanes–EtOAc, 1:1).
IR (CHCl3): 2938, 1422, 1381, 1329, 1272 cm–1.
1H NMR (400 MHz): d = 9.41 (s, 1 H), 8.73 (d, J = 5.6 Hz, 1 H),
7.81 (d, J = 6.0 Hz, 1 H), 3.23–3.19 (m, 4 H), 2.11–2.05 (m, 4 H).
Single-Crystal X-ray Structure of 3m
Grown by slow diffusion of EtOAc into a solution of compound 3m
in CH2Cl2 to yield a prism. The compound crystallizes in the mon-
oclinic crystal system; space group P1n1; a = 7.1628(15) Å,
b = 5.0923(12) Å, c = 15.510(3) Å; V = 565.7(2) Å3; Z = 2;
dcalcd = 1.352 g/cm3, F(000) = 240, 2q range 2.63–26.47°, R indices
(all data) R1 = 0.0566, wR2 = 0.0883.
13C NMR (100 MHz): d = 159.58, 156.50, 153.52, 146.42 (2×),
120.82 (2×), 33.31 (2×), 22.51 (2×).
HRMS (ESI): m/z [M + 1]+ calcd for C11H12N3: 186.1031; found:
186.1030.
5-Methyl-benzo[a]phenazine (3n)
Yield: 98 mg (80%); mp 174–175 °C (recrystallized from hexanes
and EtOAc); Rf = 0.3 (hexanes–EtOAc, 2:1).
IR (CHCl3): 3033, 1331, 1033, 781 cm–1.
Anal. Calcd for C11H11N3: C, 71.33; H, 5.99; N, 22.69. Found: C,
71.49; H, 6.21; N, 22.78.
Synthesis 2011, No. 19, 3143–3151 © Thieme Stuttgart · New York

3150
M.-Y. Chang et al.
PAPER
7,8,9,10-Tetrahydro-2-(7,8,9,10-tetrahydro-6H-cyclohep-
ta[b]quinoxalin-3-yl)-6H-cyclohepta[b]quinoxaline (7b)
Yield: 158 mg (80%); mp >230 °C (recrystallized from hexanes and
EtOAc); Rf = 0.2 (hexanes–EtOAc, 1:1).
6,7,8,9,10,11,12,13,14,15-Decahydro-2,5,16-triaza-cyclodode-
ca[b]naphthalene (6b)
Yield: 121 mg (90%); mp 96–97 °C (recrystallized from hexanes
and EtOAc); Rf = 0.2 (hexanes–EtOAc, 1:1).
IR (CHCl3): 2944, 1429, 1363, 1281 cm–1.
IR (CHCl3): 3032, 1582, 1410, 1324 cm–1.
1H NMR (400 MHz): d = 9.50 (s, 1 H), 8.72 (d, J = 5.6 Hz, 1 H),
7.82 (d, J = 6.0 Hz, 1 H), 3.32–3.22 (m, 4 H), 1.98–1.91 (m, 4 H),
1.53–1.30 (m, 12 H).
1H NMR (400 MHz): d = 8.34 (s, 2 H), 8.09 (s, 4 H), 3.27–3.24 (m,
8 H), 1.99–1.95 (m, 4 H), 1.90–1.82 (m, 8 H).
13C NMR (100 MHz): d = 159.67 (2×), 159.25 (2×), 140.96 (2×),
140.49 (2×), 140.34 (2×), 129.02 (2×), 128.46 (2×), 126.67 (2×),
38.86 (2×), 38.84 (2×), 31.99 (2×), 26.96 (2×), 26.93 (2×).
HRMS (ESI): m/z [M + 1]+ calcd for C26H27N4: 395.2236; found:
395.2238.
13C NMR (100 MHz): d = 160.12, 156.14, 153.54, 146.44 (2×),
120.82 (2×), 32.43 (2×), 27.95 (2×), 26.38 (2×), 25.48 (2×), 23.05
(2×).
HRMS (ESI): m/z [M + 1]+ calcd for C17H24N3: 270.1970; found:
270.1971.
Anal. Calcd for C26H26N4: C, 79.16; H, 6.64; N, 14.20. Found: C,
79.38; H, 6.84; N, 14.51.
Anal. Calcd for C17H23N3: C, 75.80; H, 8.61; N, 15.60. Found: C,
76.02; H, 8.79; N, 15.49.
2-Ethyl-7-(2-ethyl-1,2,3,4-tetrahydrophenazin-7-yl)-1,2,3,4-tet-
rahydrophenazine (7c)
Yield: 165 mg (78%); mp 129–130 °C (recrystallized from hexanes
and EtOAc); Rf = 0.2 (hexanes–EtOAc, 1:1).
Mixture of 8-Methyl-6,7,8,9-tetrahydropyrido[3,4-b]quinoxa-
line and 7-Methyl-6,7,8,9-tetrahydropyrido[3,4-b]quinoxaline
(6c)
Yield: 70 mg (70%); Rf = 0.2 (hexanes–EtOAc, 1:1).
IR (CHCl3): 3066, 2897, 1587, 1465, 1359 cm–1.
1H NMR (400 MHz): d = 9.39 (s, 1 H), 8.71 (d, J = 5.6 Hz, 1 H),
7.79 (d, J = 6.0 Hz, 1 H), 3.33–3.26 (m, 2 H), 3.19–3.10 (m, 1 H),
2.78 (dd, J = 10.8, 18.0 Hz, 1 H), 2.21–2.10 (m, 2 H), 1.74–1.63 (m,
1 H), 1.20 (d, J = 6.4 Hz, 3/2 H), 1.19 (d, J = 6.4 Hz, 3/2 H).
1H NMR (400 MHz): d = 8.32 (s, 2 H), 8.07 (s, 4 H), 3.37–3.24 (m,
4 H), 3.18–3.09 (m, 2 H), 2.77 (ddd, J = 2.4, 10.8, 13.2 Hz, 2 H),
2.23–2.16 (m, 2 H), 1.96–1.87 (m, 2 H), 1.72–1.62 (m, 2 H), 1.57–
1.49 (m, 4 H), 1.05 (t, J = 7.2 Hz, 6 H).
13C NMR (100 MHz): d = 159.19 (1/2×), 159.16 (1/2×), 156.12 (1/
2×), 156.08 (1/2×), 153.55 (1/2×), 153.52 (1/2×), 146.44 (1/2×),
146.41 (1/2×), 143.71 (1/2×), 143.68 (1/2×), 136.54 (1/2×), 136.50
(1/2×), 120.81 (1/2×), 120.78 (1/2×), 41.94 (1/2×), 41.59 (1/2×),
32.84 (1/2×), 32.46 (1/2×), 30.55 (1/2×), 30.45 (1/2×), 29.02 (1/2×),
28.93 (1/2×), 21.47.
13C NMR (100 MHz): d = 154.79, 154.66, 154.38, 154.24, 141.40,
141.37, 140.81 (2×), 140.37, 140.34, 128.98 (2×), 128.47 (2×),
126.53 (2×), 39.45 (2×), 35.81 (2×), 32.42 (2×), 28.84 (2×), 28.54
(2×), 11.46 (2×).
HRMS (ESI): m/z [M + 1]+ calcd for C28H31N4: 423.2549; found:
423.2550.
Synthesis of Skeleton 7; General Procedure
Anal. Calcd for C28H30N4: C, 79.59; H, 7.16; N, 13.26. Found: C,
79.87; H, 7.39; N, 13.41.
NBS (187 mg, 1.05 mmol) was added to a stirred solution of com-
pound 1f, 1g, or 1k (1.0 mmol) in AcOH (5 mL) at r.t., and the re-
action mixture was stirred at reflux for 2–4 h. The reaction was
cooled to r.t. and 3,3¢-diaminobenzidine (110 mg, 0.5 mmol) was
added to the reaction mixture at r.t. The reaction mixture was further
stirred at reflux for 2–4 h and then cooled to r.t. again. CH2Cl2 (20
mL) and sat. aq NaHCO3 (10 mL) were added to the reaction mix-
ture, which was cooled in an ice bath. The residue was extracted
with CH2Cl2 (3 × 20 mL) and the combined organic layers were
washed with brine (3 × 10 mL), dried, filtered, and evaporated to af-
ford the crude product. Purification on silica gel (hexanes–EtOAc,
2:1→1:2) afforded compounds 7a–c.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.
Acknowledgment
The authors would like to thank the National Science Council of the
Republic of China for its financial support (NSC 99–2113-M-037–
006-MY3). The project was also supported by a grant from the
Kaohsiung Medical Research Foundation (KMU-Q100004).
2,3-Dihydro-6-(2,3-dihydro-1H-cyclopenta[b]quinoxalin-7-yl)-
1H-cyclopenta[b]quinoxaline (7a)
Yield: 73 mg (43%); mp >230 °C (recrystallized from hexanes and
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Aghapoor, K.; Mohsenzadeh, F. Catal. Commun. 2007, 8,
389.
(11) For Ni nanoparticles, see: Kumar, A.; Kumar, S.; Saxena,
A.; De, A.; Mozumdar, S. Catal. Commun. 2008, 9, 778.
(17) (a) Emoto, T.; Kubosaki, N.; Yamagiwa, Y.; Kamikawa, T.
A. Tetrahedron Lett. 2000, 41, 355. (b) de Andrade-Neto,
V. F.; Goulart, M. O. F.; da Silva Filho, J. F.; da Silva, M. J.;
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(18) Makgatho, M. E.; Anderson, R.; O’Sullivan, J. F.; Egan, T.
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(19) Wang, W. Y.; Preville, P.; Morin, N.; Mounir, S.; Cai, W. Z.;
Siddiqui, M. A. Bioorg. Med. Chem. Lett. 2000, 10, 1151.
(20) CCDC 807121 (3b), 810169 (3h), 818140 (3m), and 818141
(3o) contain the supplementary crystallographic data for this
paper. This data can be obtained free of charge via
www.ccdc.cam.ac.uk/conts/retrieving.html [or from the
CCDC, 12 Union Road, Cambridge CB2 1EZ, UK; fax:
+44(1223)336033; e-mail: deposit@ccdc.cam.ac.uk].
Synthesis 2011, No. 19, 3143–3151 © Thieme Stuttgart · New York