New synthesis of diazepino[3,2,1-ij]quinoline and pyrido[1,2,3-de] quinoxalines via addition-elimination followed by cycloacylation

Article abstract of DOI:10.1002/jhet.1594

This paper describes a convenient and efficient synthesis of new fused tricyclic diazepino[3,2,1-ij]quinolines and substituted pyrido[1,2,3-de] quinoxalines. o-Phenylenediamines are transformed in the tricycle nucleus in only a few-step synthetic sequence

Full text of DOI:10.1002/jhet.1594

Month 2013
New Synthesis of Diazepino[3,2,1-ij]quinoline and Pyrido[1,2,3-de]
quinoxalines via Addition–Elimination Followed by Cycloacylation
*
*
Pier Giovanni Baraldi, Emanuela Ruggiero, and Mojgan Aghazadeh Tabrizi
Department of Pharmaceutical Sciences, University of Ferrara, Via Fossato di Mortara 17-19, 44121, Ferrara, Italy
*
E-mail: baraldi@dns.unife.it
Received October 4, 2011
DOI 10.1002/jhet.1594
Published online 00 Month 2013 in Wiley Online Library (wileyonlinelibrary.com).
O
COOC2H5
COOC2H5
1) acrylic acid, 2) DEEM, 3) PPA
N
85%
HN
O
O
NH2
NH2
1) ketone; NaBH4, 2) DEEM, 3) PPA
60-70%
N
O
HN
R1 R
R
COOC2H5
N
1) ethyl bromoacetate, 2) DEEM, 3) PPA
60-70%
HN
O
This paper describes a convenient and efficient synthesis of new fused tricyclic diazepino[3,2,1-ij]
quinolines and substituted pyrido[1,2,3-de]quinoxalines. o-Phenylenediamines are transformed in the
tricycle nucleus in only a few-step synthetic sequence to produce ethyl 2,8-dioxo-1,2,3,4-tetrahydro-8H
[1,4]diazepino[3,2,1-ij]quinoline-7-carboxylate, ethyl 8-oxo-1,2,3,4-tetrahydro-8H-[1,4]diazepino[3,2,1-ij]
quinoline-7-carboxylate and ethyl 2,7-dioxo-2,3-dihydro-1H,7H-pyrido[1,2,3-de]quinoxaline-6-carboxylate.
The method is economical and simple to perform.
J. Heterocyclic Chem., 00, 00 (2013).
INTRODUCTION
the cost and readily availability of o-phenylenediamines
variously substituted.
Bicyclic and tricyclic quinolone derivatives potentially
useful as antibacterial agents in medicinal chemistry
represent an attractive starting point for the design of phar-
macological targets. Many publications have reported the
importance role of 4-quinolones (Fig. 1) in various biological
areas, as demonstrated by compounds 1 (A-65282, antitumor
agent) [1], 2 (ofloxacin, chemotherapeutic agent) [2], and
pyridoquinoxalines 3 (inhibitors of human cytomegalovirus
polymerase) [3].
In this paper, we describe the synthesis of a number
of fused tricyclic quinolones and pyridoquinoxalines
(analogues 4–6, Fig. 2) of pharmacological interest in this
chemical series. This simple method for the preparation
of compounds 4–6, as illustrated in Schemes 1, 3, and 4,
could be synthetically accessible with a good number of
rapid functionalization and increase hit rates at biological
targets. The choice of the starting material was based on
RESULTS AND DISCUSSION
The 2,8-dioxo-1,2,3,4-tetrahydro-8H[1,4]diazepino[3,2,1-
ij]quinoline-7-carboxylate 4 was prepared as outlined in
Scheme 1 by a three-step synthetic sequence. Condensation
of o-phenylenediamine with acrylic acid yielded lactam 7
[4] in 68% yield. Subsequent reaction with diethyl ethox-
ymethylene malonate (DEEM) at 140ꢀC furnished the
methylenemalonate 8 in 90% yields. A thermally induced
cyclization of 8 in polyphosphoric acid (PPA) for 30 min
resulted in target diazepinoquinolone 4 in 95% yields.
Our initial route to prepare the targets 5a–c is shown
in Scheme 2. The formation of 2,3-dihydro-1H-benzo[b]
[1,4]diazepines 9a–c proceeded in 80–95% yield, from
© 2013 HeteroCorporation

P. G. Baraldi, E. Ruggiero, and M. Aghazadeh Tabrizi
Vol 000
O
N
O
Scheme 2
F
COOH
F
COOH
R
R1
R2
H
N
NH2
NH2
N
N
N
appropriate ketones
10 mol% NBS, 40°C
H2N
O
N
O
H3C
CH3
N
R
9a-c
1, A-65282
2, Ofloxacine
DEEM
130°C
O
N
x
COOC2H5
R
COR
C2H5OOC
COOC2H5
COOC2H5
H
N
N
R1
R2
HN
O
NH2
N
R
3
10
11
Figure 1. Structures of 4-quinolones endowed with pharmacological
a: R = R1 = methyl, R2 = H
activity.
b: RR1 = cyclopentyl, R2R = cyclopentyl
c: R = phenyl, R1 = methyl, R2 = H
O
N
O
N
O
N
COOC2H5
COOC2H5
COOC2H5
Scheme 3. Synthesis of ethyl 2,3,4,8-tetrahydro-8-oxo-1H[1,4]diazepino
[3,2,1-ij]quinoline-7-carboxylate 5a–c.
HN
R1
HN
HN
O
R
R
O
R
R1
R2
H
N
R
H
N
1
2
R1
4
5a-c
6a-c
NaBH4, CH3OH
2 h, 75-80%
3
R2
5
N
H
Figure 2. Diazepino[3,2,1-ij]quinoline and pyridoquinoxaline structures.
4
N
R
R
12a-c
9a-c
Scheme 1. Synthesis of ethyl 2,3,4,8-tetrahydro-2,8-dioxo-1H[1,4]diazepino
[3,2,1-ij]quinoline-7-carboxylate 4.
DEEM, 140°C
85-90%
H
N
O
O
NH2
NH2
O
COOC2H5
OH
C2H5OH, Rf, 68%
8
7
COOC2H5
N
H
C2H5OOC
R
N
5
N 4
6
7
PPA, 130°C, 1 h
35-40%
HN1
R1
R2
R
3
DEEM, 140°C
90%
2
N
R
H
R2
5a-c
R
R1
13a-c
O
8
H
N
O
a: R = R1 = methyl, R2 = H
7
b: RR1 = cyclopentyl, R2R = cyclopentyl
c: R = phenyl, R1 = methyl, R2 = H
COOC2H5
PPA, 130°C
1 h, 95%
6
5
N
N
4
HN1
O
the iminic carbon nitrogen double bond yielding diethyl 2-
[(2-aminophenylamino)methylene]malonate 10.
C2H5OOC
2
3
COOC2H5
The alternative route to synthesize the target compounds
5a–c as shown in Scheme 3 was achieved by reduction of car-
bon nitrogen double bond of compounds 9a–c using sodium
borohydride (NaBH4) [6,7] to give 1,5-benzodiazepines
12a–c in 75–80% yield. The transfer hydrogenation of
prochiral imine 9b furnished a mixture of syn/anti diastereo-
mers (3/1) that were separated by column chromatography
on silica gel to give the syn-isomer 12b as major diastereo-
mer. The NMR studies by NOE difference (NOEDIFF)
4
8
o-phenylenediamine simply by heating with aromatic
(acetophenone), aliphatic acyclic (acetone), and cyclic
ketones (cyclopentanone) in the presence of 2 mol% NBS
as a catalyst [5]. Subsequent addition–elimination reaction
with DEEM, in contrast to the synthesis of methylenemalo-
nate 8, did not produce 11 but underwent hydrolysis of
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2013
New Synthesis of Diazepino[3,2,1-ij]quinoline and Pyrido[1,2,3-de]quinoxalines
Scheme 4. Synthesis of ethyl 1,2,3,7-tetrahydro-2,7-dioxopyrido[1,2,3-
de]quinoxaline-6-carboxylate 6a–c.
experiments confirmed the syn-conformation showing the
presence of NOE enhancements between H-3 (d = 2.39 ppm)
and H-4 (d = 4.43 ppm) protons. Furthermore, the saturation
of H-4 (d = 4.43 ppm) protons did not reveal NOE with the
cyclopentyl hydrogens.
H
N
O
R
NH2
R
O
Br
O
NH2
TEA, 80 °C
80%
N
H
14a-c
In the case of 1,5-benzodiazepine 12c unexpectedly, the
syn-diastereomer 12c was the only compound obtained from
hydrogenation by NaBH4. The configuration of 12c was
assessed through NOEDIFF experiments. The saturation of
C2-Me (d = 1.64 ppm) protons resulted in NOE enhance-
ments at H-4 (d = 4.22 ppm), suggesting a cis relationship
a
b
c
: R = H
: R = F
: R = Cl
DEEM, 140°C
70-75%
1
between the methyl at C-2 and H-4. The H- and 13C-
H
H
N
R
N
O
R
O
NMR data of this compound fit completely to that reported
in literature for the syn-isomer [8]. A possible reaction
mechanism may be the transfer of hydride ion on the same
side of the methyl group due to steric hindrance of the phenyl
ring at C-2 position.
PPA, 130 °C, 1 h
50-55%
N
N
C2H5OOC
O
COOC2H5
15a-c
COOC2H5
The 5-methylenemalonates 13a–c were obtained from
condensation with DEEM at 140ꢀC for 2 h yielding 13a–c
(85–90%). The regioselective addition of DEEM at N-5
position was favored because of the less steric hindrance
present at the 4-position than that of 2-position (Scheme 3).
Subsequently, cyclization was achieved using PPA at
130ꢀC in a short time to give target compounds 5a–c in
35–40% yields [9,10]. The chemical identity of final
compounds 5a–c has been confirmed by 1H-NMR and MS
spectra. The NMR NOEDIFF studies were carried out on
compounds 5a–c to acquire information about the C-4
substituents. Compounds 5a–c showed NOE enhancement
from the position 6-CH to the 4-CH protons on the tricyclic
nucleus, confirming the addition of methylmalonate chain
on the NH close to the less steric hindrance carbon atom.
In this paper, we also report a simple method for the
synthesis of ethyl pyrido[1,2,3-de]quinoxaline-6-carboxy-
lates. Only few examples of 9-substituted-3,4-dihydroqui-
noxalin-2(1H)-ones have been reported in literature, and
their synthesis has been generally carried out by using
2-nitrobenzenamine or 1-fluoro-2-nitrobenzene as starting
materials [11–13].
As outlined in Scheme 4, treatment of o-phenylenedia-
mines with methyl 2-bromoacetate in the presence of TEA
at 80ꢀC furnished the 3,4-dihydroquinoxalin-2(1H)-ones
(14a–c) [12] in 80% yields. In analogy to the synthesis of
previous tricycles, addition of DEEM to 14a–c yielded
(70–75%) diethyl [(3-oxo-3,4-dihydroquinoxalin-1(2H)-yl)
methylene]malonates 15a–c; this addition–elimination reac-
tion is followed by cycloacylation in PPA at high tempera-
ture to yield the target compounds 6a–c. The presence of
(9-F, 9-Cl) on the quinoxaline nucleus, in compounds 6b
and 6c, was confirmed by their 1H-NMR spectra; in addition,
19F-NMR resonances were well resolved for fluorine deriva-
tive 6b that consisted of three signals at À114.070,
À114.094, and À114.119 ppm with JHF (H-8) = JHF
(H-9) = 10Hz (equal intensity), which confirms the presence
6a-c
of fluorine on the 9-position. The biological activity of
synthesized compounds would be reported in due course.
EXPERIMENTAL
Reagent grade solvents were dried according to standard
techniques. Sodium sulfate was used as a drying agent for water
containing organic phases. All reported yields are of isolated
products and are not optimized. Reactions were routinely monitored
by TLC on silica gel (F245 Merck plates). Chromatographic spots
were visualized by UV light. Purification of crude compounds and
separation of reaction mixtures were carried out by column chroma-
tography on silica gel 60 [230–400 mesh from Merck (Rome,
Italy)]. Melting points (uncorrected) were determined in a 240
Buchi-Tottoli melting point apparatus (Butchi Italia S.R.L, Milano,
Italy). Chemical shifts (d) are reported in parts per million (ppm)
relative to the solvent central peak. 1H-NMR spectra were recorded
at 200 or 400 MHz on a Bruker AC 200 spectrometer (Bruker Italia,
Milano, Italy). ESI/MS was performed with an Agilent 1100 Series
LC/MSD model (Agilent Technologies Italia S.P.A., Milano, Italy)
in positive scan mode. The molecular weights from the MS spectra
were in full agreement with the proposed chemical structures of
target compounds. Elemental analysis data for final compounds
were obtained from the micro-analytical laboratory of the Depart-
ment of Chemistry, Ferrara University, and were within Æ0.40 of
the theoretical values for the formulas given.
Synthesis of 4,5-dihydro-1H-benzo[b][1,4]diazepin-2(3H)-
one (7). A mixture of 1,2-phenyldiamine (0.018 mol) and 60%
aqueous acrylic acid (0.027 mol) dissolved in water (3.5 mL)
and conc. hydrochloric acid (3.5 mL) was stirred at 70ꢀC for 3 h
(TLC). The solvent was evaporated by distillation, basified with
conc. ammonium hydroxide. The reaction mixture was
partitioned between H2O and ethyl acetate (EtOAc). The EtOAc
layer was washed with brine and dried over Na2SO4. The
solvent was evaporated under reduced pressure. The desired
product was crystallized from EtOAc to afford 4,5-dihydro-1H-
benzo[b][1,4]diazepin-2(3H)-one 7 (2 g, 68%) as pale white
solid, mp 138ꢀC, MS m/z 163 (MH+). 1H-NMR (200 MHz,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

P. G. Baraldi, E. Ruggiero, and M. Aghazadeh Tabrizi
Vol 000
DMSO): d 2.72 (t, J = 5.4 Hz, 2H, H-3); 3.65 (m, 2H, H-4); 4.10
(br s, 1H, NH); 7.02–6.70 (m, 4H); 7.99 (br s, 1H, CONH).
Synthesis of diethyl 2-[(1,2,3,4-tetrahydro-2-oxobenzo[b]
yields. Compounds 13a–c were used in the next step without
purification.
General synthetic procedure for ethyl 2,3,4,8-tetrahydro-8-oxo-
[1,4]diazepin-5-yl)methylene]malonate (8).
A mixture of
1H-[1,4]diazepino[3,2,1-ij]quinoline-7-carboxylate (5).
Starting
4,5-dihydro-1H-benzo[b][1,4]diazepin-2(3H)-one 7 (0.8 g, 0.005 mol)
and DEEM (1 g, 0.005 mol) was heated at 140ꢀC for 1h. The
reaction mixture was poured into n-hexane, and the precipitate
was collected by filtration to give the desired compound as a pale
white solid (90%) that was filtered and used without purification in
the next step.
with diethyl 2-((1,2,3,4-tetrahydro-2,2,4-trimethylbenzo[b]
[1,4]diazepin-5-yl)methylene)malonates (13a–c), the title
compounds were prepared in a manner analogous to that
described for compound 4.
Ethyl 2,3,4,8-tetrahydro-2,2,4-trimethyl-8-oxo-1H-[1,4]diazepino
[3,2,1-ij]quinoline-7-carboxylate (5a). Purification on silica gel
column: EtOAc : n-hexane 7/3, yellow solid (40%), mp 126ꢀC, MS
m/z 315 (MH+). Anal. Calcd for C18H22N2O3: C, 68.77; H, 7.05; N,
8.91. Found: C, 69.07; H, 7.24; N, 8.72. 1H-NMR (400 MHz,
CDCl3): d 1.16 (s, 3H, CH3-2); 1.28 (s, 3H, CH3-2); 1.41 (t,
J= 7.2 Hz, 3H, CH3-ester); 1.95 (m, 1H, H-3); 2.07 (d d, J=14Hz,
J= 3.2 Hz, 1H, H-3); 3.46 (br s, 1H, NH); 4.39 (q, 2H, J=7.6Hz,
CH2-ester); 4.93 (m, 1H, H-4); 6.91 (m, 1H); 7.18 (m, 1H); 8.07
(m, 1H); 8.52 (s, 1H, H-6). 13C-NMR (100 MHz, CDCl3): d 14.5,
21.5, 30.2, 32.0, 46.7, 54.7, 60.0, 60.8, 109.5, 120.1, 123.76, 125.8,
138.0, 146.2, 166.7, 174.1.
Synthesis of ethyl 2,3,4,8-tetrahydro-2,8-dioxo-1H-[1,4]
diazepino[3,2,1-ij]quinoline-7-carboxylate (4). A mixture of
diethyl 2-((1,2,3,4-tetrahydro-2-oxobenzo[b][1,4]diazepin-5-yl)
methylene)malonate 8 (1 g, 0.003 mol) and PPA (5 g) was heated
at 130ꢀC for 1 h. The mixture was poured into ice and water to
form a white precipitate that was filtered and washed with cold
water yielding (0.8 g, 95%) the target compound as a white solid,
mp 295ꢀC, MS m/z 287 (MH+). Anal. Calcd for C15H14N2O4:
C, 62.93; H, 4.93; N, 9.79. Found: C, 63.20; H, 4.72; N, 9.98.
1H-NMR (200 MHz, DMSO):
d 1.28 (t, J= 7.2 Hz, 3H,
CH3-ester); 2.96 (t, J= 4.8 Hz, 2H, H-3); 4.23 (q, J =7.2Hz, 2H,
CH2-ester); 4.51 (t, J = 4.6 Hz, 2H, H-4); 7.50–7.25 (m, 2H);
8.10–8.00 (m, 1H): 8.53 (s, 1H, NH); 10.11 (br s, 1H, CONH).
13C-NMR (100 MHz, DMSO): d 14.3, 36.4, 52.2, 59.7,
108.5, 121.5, 124.5, 125.7, 129.0, 130.1, 130.6, 150.2,
164.3, 172.2, 173.7.
Ethyl 3-oxo-9,10,11,11a-tetrahydro-3H,7H,8aH-spiro[cyclopenta
[6,7][1,4]diazepino[3,2,1-ij]quinoline-8,1′-cyclopentane]-2-carboxylate
(5b). Purification on silica gel column: EtOAc : n-hexane 1/1,
pale yellow solid (35%), mp 109ꢀC, MS m/z 367 (MH+). Anal.
Calcd for C22H26N2O3: C, 72.11; H, 7.15; N, 7.64. Found: C,
71.76; H, 6.87; N, 7.31. 1H-NMR (400 MHz, CDCl3): d 1.43 (t,
J = 7.2 Hz, 3H, CH3-ester); 1.58–2.04 (m, 14H); 2.39 (m, 1H,
H-3); 3.72 (br s, 1H, NH); 4.39 (q, J = 7.2 Hz, 2H, CH2-ester);
4.43 (m, 1H, H-4); 6.80 (m, 1H); 7.19 (m, 1H); 7.96 (m, 1H);
8.52 (s, 1H, H-6).
Ethyl 2,3,4,8-tetrahydro-2-methyl-8-oxo-2,4-diphenyl-1H-[1,4]
diazepino[3,2,1-ij]quinoline-7-carboxylate (5c). Purification on
silica gel column: EtOAc : n-hexane 8/2, pale white solid (40%), mp
150ꢀC, MS m/z 439 (MH+). Anal. Calcd for C28H26N2O3: C, 76.69;
H, 5.98; N, 6.39. Found: C, 76.35; H, 5.76; N, 6.68. 1H-NMR
(400 MHz, CDCl3): d 1.28 (t, J= 7.6 Hz, 3H, CH3-ester); 1.64
(s, 3H, CH3-2); 2.72 (d d, J= 15.2 Hz, J= 2 Hz, 1H, H-3); 3.37
(d d, J= 15.2 Hz, J= 8.4 Hz, 1H, H-3); 3.77 (br s, 1H, NH); 4.25
(q, J=7.2Hz, 2H, CH2-ester); 5.99 (d d, J=8.4Hz, J=1.6Hz, 1H,
H-4); 6.98 (m, 1H); 7.29–7.11 (m, 11H); 8.11 (s, 1H, H-6); 8.16
(m, 1H).
Synthesis of 2,3-dihydro-1H-benzo[b][1,4]diazepines (9). Com-
pounds 9a–c were obtained as described in literature [4].
General synthetic procedure for of 2,3,4,5-tetrahydro-1H-
benzo[b][1,4]diazepine (12). A mixture of benzodiazepine 9
(0.02 mol), methanol (50 mL), and sodium borohydride
(0.02 mol) was stirred at room temperature for 2 h (TLC) (for
compound 12c, the reaction mixture was stirred at 40ꢀC for
8 h). Methanol was evaporated under reduced pressure, and the
reaction mixture was partitioned between H2O and ethyl acetate
(EtOAc). The organic layer was washed with brine, dried over
Na2SO4, and concentrated in vacuo. The resulting product was
purified on silica gel column.
2,3,4,5-Tetrahydro-2,2,4-trimethyl-1H-benzo[b][1,4]diazepine
(12a). Pale white solid (80%), mp 60–61ꢀC, MS m/z 191 (MH+).
1H-NMR (200 MHz, CDCl3): d 1.08 (s, 3H, CH3-2); 1.22 (d,
J = 6.4 Hz, 3H, CH3-4); 1.32 (s, 3H, CH3-2); 1.66–1.53 (m, 2H,
H-3); 3.22 (m, 1H, H-4); 3.26 (br s, 2H, NH); 6.79–6.61 (m, 4H).
2,3,3a,4,9,10a-Hexahydro-1H-spiro[benzo[b]cyclopenta[e]
[1,4]diazepine-10,1′-cyclopentane] (12b). Pale yellow solid
(75%), mp 70ꢀC, MS m/z 243 (MH+). 1H-NMR (200 MHz,
CDCl3): d 1.2–2.7 (m, 15H); 3.5 (m, 1H, H-4); 4.00 (br s, 2H,
General synthetic procedure for 3,4-dihydroquinoxalin-2(1H)-
one (14). Starting with (4-substituted)-o-phenylenediamine, the title
compounds were prepared as described in literature [12].
3,4-Dihydroquinoxalin-2(1H)-one (14a). Purified on silica
gel column (EtOAc : n-hexane 1/1), tan solid (55%), mp 127–
1
129ꢀC, MS m/z 149 (MH+). H-NMR (200 MHz, CDCl3): d 3.40
NH); 6.61–6.70 (m, 4H).
2,3,4,5-Tetrahydro-2-methyl-2,4-diphenyl-1H-benzo[b][1,4]
(br s, 1H, NH); 3.99 (s, 2H, CH2); 6.93–7.20 (m, 4H); 8.92 (br s,
1H, NHCO).
diazepine (12c). Pale white solid (80%), mp 132–133ꢀC, MS
m/z 315 (MH+). 1H-NMR (400 MHz, CDCl3): d 1.64 (s, 3H,
CH3-2); 1.88 (d d, J = 13.6 Hz, J = 2 Hz, 1H, H-3); 2.44 (m,
1H, H-3); 3.83 (br s, 2H, NH); 4.22 (d d, J = 13 Hz,
J = 12 Hz, 1H, H-4); 6.83 (m, 4H); 7.46–7.25 (m, 8H); 7.73
(m, 2H). 13C-NMR (100 MHz, CDCl3): d 23.7, 55.4, 57.2,
57.7, 120.6, 122.3, 125.3, 126.7, 127.0, 127.7, 128.5, 128.8,
137.2, 139.7, 145.2, 150.3.
6-Fluoro-3,4-dihydroquinoxalin-2(1H)-one (14b). Purified
on silica gel column (EtOAc : n-hexane 8/2), tan solid (60%),
mp 245–246ꢀC, MS m/z 167 (MH+). 1H-NMR (200 MHz,
CDCl3): d 3.68 (s, 2H, CH2); 5.88 (br s, 1H, NH); 7.05–7.21
(m, 2H); 7.84 (m, 1H); 10.32 (br s, 1H, NHCO).
6-Chloro-3,4-dihydroquinoxalin-2(1H)-one (14c). Purified on
silica gel column (EtOAc: n-hexane 1/1), tan solid (55%),
mp 214–215ꢀC, MS m/z 183 (MH+). 1H-NMR (200 MHz,
CDCl3): d 3.65 (s, 2H, CH2); 5.80 (br s, 1H, NH); 6.99–7.05
(m, 2H); 7.20 (m, 1H); 10.00 (br s, 1H, NHCO)
General synthetic procedure for diethyl 2-[(1,2,3,4-tetrahydro-
2,2,4-trimethylbenzo[b][1,4]diazepin-5-yl)methylene]malonate
(13a–c). Starting with 3,4,5-tetrahydro-2,2,4-trimethyl-1H-benzo
[b][1,4]diazepines 12, the title compounds were prepared in a
manner analogous to that described for compound 8 in 85–90%
General synthetic procedure for diethyl 2-[(2,3-dihydro-2-
oxoquinoxalin-4(1H)-yl)methylene]malonate (15). Starting with
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2013
New Synthesis of Diazepino[3,2,1-ij]quinoline and Pyrido[1,2,3-de]quinoxalines
3,4-dihydroquinoxalin-2(1H)-one (14a–c), the title compounds
were prepared (70–75%) in a manner analogous to that
described for compound 8. Compounds 15a–c were used in
the next step without purification.
J = 7.2 Hz, 2H, CH2-ester); 5.01 (s, 2H, CH2-2); 7.13 (s, 1H);
7.71 (m, 1H); 8.51 (s, 1H); 11.16 (br s, 1H, NHCO).
General synthetic procedure for ethyl 1,2,3,7-tetrahydro-
2,7-dioxopyrido[1,2,3-de]quinoxaline-6-carboxylate (6).
Starting with diethyl 2-((2,3-dihydro-2-oxoquinoxalin-4(1H)-yl)
methylene)malonates 15a–c, the title compounds were prepared
in a manner analogous to that described for compound 4.
Ethyl 1,2,3,7-tetrahydro-2,7-dioxopyrido[1,2,3-de]quinoxaline-
6-carboxylate (6a). Purified on silica gel column (EtOAc : methanol
9/1), white solid. (55%), mp >300ꢀC, MS m/z 273 (MH+). Anal.
Calcd for C14H12N2O4: C, 61.76; H, 4.44; N, 10.29. Found: C,
61.77; H, 4.45; N, 10.26. 1H-NMR (200 MHz, CDCl3): d 1.28
(t, J= 7 Hz, 3H, CH3-ester), 4.17 (q, J=7Hz, 2H, CH2-ester); 5.01
(s, 2H, CH2-2); 7.37–7.15 (m, 2H); 7.71 (m, 1H); 8.51 (s, 1H, H-5);
11.16 (br s, 1H, NHCO). 13C-NMR (100 MHz, DMSO): d 14.3,
52.0, 59.8, 111.0, 116.6, 118.9, 125.2, 126.0, 127.6, 129.3, 147.2,
162.2, 164.3, 172.2.
Acknowledgments. The authors are grateful to Dr. Alberto Casolari
for his support in the NMR studies. Funding for this study was
provided by the Ministero dell’Università e della Ricerca Scientifica
e Tecnologica, Rome, Italy.
REFERENCES AND NOTES
[1] Kang, D.H; Kim, J.S.; Jung, M.J.; Lee, E.S.; Jahng, Y.;
Kwona, Y.; Nab, Y. Bioorg Med Chem Lett 2008, 18, 1520.
[2] Thys, J.P.; Jacobs, F.; Byl, B. Eur J Clin Microbiol Infect Dis
1991, 10, 304.
[3] Tanis, S.P.; Strohbach, J.W.; Parker, T. T.; Moon, M.W.;
Thaisrivongs, S.; Perrault, W.R.; Hopkins, T.A.; Knechtel, M.L; Nancee,
L.O.; Wieber, J.L.; Stephanski, K.J.; Wathen, M.W. Bioorg Med Chem
Lett 2010, 20, 1994.
Ethyl 9-fluoro-1,2,3,7-tetrahydro-2,7-dioxopyrido[1,2,3-de]
quinoxaline-6-carboxylate (6b). Purified on silica gel column
(EtOAc), white solid (50%), mp >300ꢀC, MS m/z 291 (MH+).
Anal. Calcd for C14H11FN2O4: C, 57.93; H, 3.82; N, 9.65.
Found: C, 57.96; H, 3.61; N, 9.62. 1H-NMR (200 MHz,
CDCl3): d 1.27 (t, J = 7.4 Hz, 3H, CH3-ester), 4.18 (q,
J = 7.22 Hz, 2H, CH2-ester); 5.02 (s, 2H, CH2-2); 7.17–7.11 (m,
1H); 7.56–7.51 (m, 1H); 8.55 (s, 1H, H-5); 11.18 (br s, 1H,
CONH). 16F-NMR (397 MHz, DMSO): d = À114.094 (t, 1 F,
J = 10 Hz, F-9).
Ethyl 9-chloro-1,2,3,7-tetrahydro-2,7-dioxopyrido[1,2,3-de]
quinoxaline-6-carboxylate (6c). Purified on silica gel column
(EtOAc), white solid (50%), mp 292ꢀC, MS m/z 307 (MH+).
Anal. Calcd for C14H11ClN2O4: C, 54.83; H, 3.62; N, 9.13.
Found: C, 54.79; H, 3.60; N, 9.11. 1H-NMR (200 MHz,
[4] Bachmann, G.; Heisey, L. V. J Am Chem Soc 1949, 71, 1985.
[5] Kuo, C.W.; More, S. V.; Yao, C.F. Tetrahedron Lett 2006,
47, 8523.
[6] Morales, H.R. Heterocycles 1986, 24, 135.
[7] Venkatraj, M.; Jeyaraman, R.; Ponnuswamy, S. Indian J
Chem, Section B: Organic Chemistry Including Medicinal Chemistry,
2006, 45, 1531.
[8] Han, Z.Y.; Xiao, H.; Gong, L.Z. Bioorg Med Chem Lett 2009, 19, 3729.
[9] Gould, R.; Jacobs, W.A.; J Am Chem Soc, 1939, 61, 2890.
[10] Lappin, G. J Am Chem Soc 1948, 70, 3348.
[11] Anderson, D. J.; Thomas J.; Bundy, G. L.; Ciske, F. L.; Farrell,
J. R.; Graber, D. R.; Genin, M. J.; Judge, T. M.; Moon, M. W.; Schnute,
M. E. PCT Int. Appl. WO 2002004445, 2002.
[12] Tuerdi, H.; Chao, H. J.; Qiao, J. X.; Wang, T. C.; Gungor, T.
Pat. Appl. U.S. 20050261244, 2005.
[13] Strohbach, J. W.; Tanis, S.P.; Moon, M. W.; Nieman, J. A.;
Beauchamp, T. J.; Northuis, J. M.; McGhee, W. D. PCT Int. Appl. WO
2003053971, 2003.
CDCl3):
d 1.25 (t, J = 7.4 Hz, 3H, CH3-ester), 4.18 (q,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet