An efficient synthesis of functionalized 6,10-dioxo-6,10-dihydro-5H- pyrido[1,2-a]quinoxalines and 6,10-dioxo-6,10-dihydropyrido[2,1-c][1,4] benzoxazines

Article abstract of DOI:10.1055/s-0029-1217542

An efficient synthesis of alkyl 8-hydroxy-6,10-dioxo-6,10-dihydro-5H- pyrido[1,2-a]quinoxaline-7-carboxylates and alkyl 8-hydroxy-6,10-dioxo-6,10- dihydropyrido[2,1-c][1,4]benzoxazine-7-carboxylates is described. This involves the reaction between malonyl dichloride and alkyl 2-[3,4-dihydro-3- oxoquinoxaline 2(1H)-ylidene]acetates or alkyl 2-(2-oxo-2H-benzo[b][1,4]oxazin- 3(4H)-ylidene)acetates in CH₂Cl₂ at room temperature. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0029-1217542

LETTER
1921
An Efficient Synthesis of Functionalized 6,10-Dioxo-6,10-dihydro-5H-pyri-
do[1,2-a]quinoxalines and 6,10-Dioxo-6,10-dihydropyrido[2,1-c][1,4]benz-
oxazines
6
, 10-Dio
s
xo-6,10-d
s
ihydro-
5
H
a
-pyrido[1,2-
a
]qu
Y
inoxalines avari,* Sanaz Souri, Mehdi Sirouspour, Mohammad J. Bayat
Chemistry Department, Tarbiat Modares University, PO Box 14115-175, Tehran 18716, Iran
Fax +98(21)82883455; E-mail: yavarisa@modares.ac.ir
Received 9 March 2009
As part of our current studies on the development of new
Abstract: An efficient synthesis of alkyl 8-hydroxy-6,10-dioxo-
6,10-dihydro-5H-pyrido[1,2-a]quinoxaline-7-carboxylates and alkyl
8-hydroxy-6,10-dioxo-6,10-dihydropyrido[2,1-c][1,4]benzoxazine-7-
carboxylates is described. This involves the reaction between malo-
routes in heterocyclic synthesis,14–16 we report17 an effi-
cient and convenient synthetic route to alkyl 8-hydroxy-
6,10-dioxo-6,10-dihydro-5H-pyrido[1,2-a]quinoxaline-7-
nyl dichloride and alkyl 2-[3,4-dihydro-3-oxoquinoxaline 2(1H)- carboxylates 4a–c and alkyl 8-hydroxy-6,10-dioxo-6,10-
ylidene]acetates or alkyl 2-(2-oxo-2H-benzo[b][1,4]oxazin-3(4H)-
dihydropyrido[2,1-c][1,4]benzoxazine-7-carboxylates 4d–h
ylidene)acetates in CH2Cl2 at room temperature.
from the reaction between malonyl dichloride and alkyl
Key words: malonyl dichloride, pyrido[1,2-a]quinoxaline, pyri-
do[2,1-c][1,4]benzoxazine, benzene-1,2-diamine, 2-aminophenol,
acetylenic ester
2-[3,4-dihydro-3-oxoquinoxaline-2(1H)-ylidene]acetates
3a–c or alkyl 2-[2-oxo-2H-benzo[b][1,4]oxazin-3(4H)-
ylidene]acetates 3d–h in CH2Cl2 at room temperature
(Scheme 1). Compounds 3 were prepared from the reac-
tion of dialkyl acetylenedicarboxylates 2a–c with ben-
zene-1,2-diamine (1a) and 2-aminophenol (1b).18,19
A
Quinoxalines and benzoxazines are privileged ring sys-
tems. Their derivatives have broad biological activities
and have been used as anticancer,1 antiviral,2 antibacterial
agents,3 and kinase inhibition agents.4,5 In addition to the
medicinal applications, quinoxalines and benzoxazines
have been used as dyes6,7 and key intermediates in the
synthesis of organic semiconductors.8,9 Quinoxalines also
play an important role as a basic skeleton for the design of
a number of antibiotics such as echinomycin, actino-
mycin, and leromycin. It has been reported that these
compounds inhibit the growth of gram-positive bacteria,
and are active against various transplantable tumors.10,11
The majority of quinoxaline and benzoxazine derivatives
are prepared by the reaction of benzene-1,2-diamine or
2-aminophenol with a 1,2-dicarbonyl compound.12,13
number of compounds closely related to 4 have been pre-
pared by reaction of compounds related to 3 with
bis(2,4,6-trichlorophenyl)malonate.20
The structures of compounds 4a–h were apparent from
their mass spectra, which displayed in each case the mo-
1
lecular ion peak at the appropriate m/z values. The H
NMR and 13C NMR spectroscopic data, as well as IR
spectra, are in agreement with the proposed structures.
1
The H NMR spectrum of 4a in DMSO-d6 showed four
singlets for methoxy (d = 3.74 ppm), CH (d = 6.08 ppm),
OH (d = 11.76 ppm), and NH (d = 11.84 ppm) protons.
The 13C NMR spectrum of 4a exhibited 14 signals in
agreement with the proposed structure. Partial assign-
ments of these resonances are given in the experimental
data. The 1H NMR and 13C NMR spectra of 4b–h are sim-
CO2R2
X
N
O
X
O
XH
5
5
MeOH, r.t.
CH2(COCl)2
CH2Cl2, r.t.
+
CO2R2
4
R1
4
R1
5 min
R1
N
H
NH2
CO2R2
CO2R2
O
OH
R2
1
2
R1
Yield (%)
4
X
R2
X
R2
R1
3
X
Yield (%)
a
b
a
b
c
Me
Et
t-Bu
a
b
c
d
e
f
98
95
98
97
96
95
98
95
NH
NH
NH
O
H
H
H
H
Me
Et
98
95
98
97
96
95
98
95
NH
NH
NH
O
H
H
H
H
Me
Et
a
b
NH
O
c
d
e
f
t-Bu
Me
t-Bu
Me
O
4-Me Me
4-Cl Me
5-Me Me
5-Cl Me
O
4-Me Me
4-Cl Me
5-Me Me
5-Cl Me
O
O
O
g
h
O
g
h
O
O
Scheme 1
SYNLETT 2009, No. 12, pp 1921–1922
x
x
.x
x
.2
0
0
9
Advanced online publication: 03.07.2009
DOI: 10.1055/s-0029-1217542; Art ID: D07309ST
© Georg Thieme Verlag Stuttgart · New York

1922
I. Yavari et al.
LETTER
(9) O’Brien, D.; Weaver, M. S.; Lidzey, D. G.; Bradley,
D. D. C. Appl. Phys. Lett. 1996, 69, 881.
(10) Bailly, C.; Echepare, S.; Gago, F.; Waring, M. Anti-Cancer
Drug Des. 1999, 14, 291.
ilar to those for 4a, except for the ester moieties, which
showed characteristic resonances in appropriate regions
of the spectra.
A tentative mechanism for this transformation is proposed
in Scheme 2. It is conceivable that the initial event is the
formation of intermediate 5 from 1 and the acetylenic es-
ter,18,19 which is converted to alkylidene quinoxaline 3.
Compound 3 is subsequently attacked by malonyl dichlo-
ride to produce 6. Intermediate 6 undergoes cyclization
reaction, HCl elimination, and keto–enol tautomerism to
generate compounds 4.
(11) Raw, S. A.; Wilfred, C. D.; Taylor, R. J. K. Chem. Commun.
2003, 18, 2286.
(12) Gilchrist, T. L. Heterocyclic Chemistry, 2nd ed.; Wiley and
Sons: New York, 1992, 272–276.
(13) Taylor, E. C.; Maryanoff, C. A.; Skotnickilc, J. S. J. Org.
Chem. 1980, 45, 2513.
(14) Yavari, I.; Souri, S.; Sirouspour, M. Synlett 2008, 1633.
(15) Yavari, I.; Souri, S. Synlett 2007, 2969.
(16) Yavari, I.; Souri, S. Synlett 2008, 1208.
(17) General Procedure for the Synthesis of Compounds 4
To a suspension of 3 (2 mmol)18 in CH2Cl2 (10 mL) was
added of malonyl dichloride (0.29 g, 2.1 mmol) at r.t. The
reaction mixture was then stirred for 15 min. The formed
precipitate was filtered off and washed with CH2Cl2 to afford
the pure product.
O
XH
X
O
OR
CO2R
CH2(COCl)2
1 + 2
H
N
H
N
H
CO2R
Compound 4a: pale yellow powder; mp 300–304 °C (dec.);
yield 0.56 g (98%). IR (KBr): nmax = 3450, 1729, 1693, 1655,
1490, 1418, 1365, 1306, 1258, 1106, 757 cm–1. 1H NMR
(500 MHz, CDCl3): d = 3.74 (3 H, s, OMe), 6.08 (1 H, s,
CH), 7.12 (1 H, d, 3J = 7.8 Hz, CH), 7.20 (1 H, t, 3J = 7.9 Hz,
CH), 7.30 (1 H, t, 3J = 8.0 Hz, CH), 9.19 (1 H, d, 3J = 7.8 Hz,
CH), 11.76 (1 H, s, OH), 11.84 (1 H, s, NH) ppm. 13C NMR
(125.7 MHz, CDCl3): d = 52.6 (OMe), 102.9 (CH), 112.4
(C), 116.4 (CH), 121.5 (CH), 122.8 (CH), 123.9 (C), 127.3
(CH), 128.1 (C), 133.0 (C), 156.2 (COH), 162.1 (CO), 162.9
(CO), 165.3 (CO2) ppm. MS: m/z (%) = 285 (20) [M – 1+],
262 (20), 236 (35), 179 (10), 123 (40), 97 (50), 83 (55), 69
(60), 57 (100), 43 (90). Anal. Calcd (%) for C14H10N2O5
(286.24): C, 58.75; H, 3.52; N, 9.79. Found: C, 58.60; H,
3.44; N, 9.65.
Compound 4d: pale yellow powder; mp 298–300 °C (dec.);
yield 0.55 g (97%). IR (KBr) nmax = 3505, 1764, 1721, 1661,
1618, 1499, 1408, 1333, 1304, 1294, 1106, 759 cm–1. 1H
NMR (500 MHz, CDCl3): d = 3.79 (3 H, s, OMe), 6.12 (1 H,
s, CH), 7.27 (1 H, t, 3J = 7.0 Hz, CH), 7.30 (1 H, d, 3J = 7.9
Hz, CH), 7.33 (1 H, t, 3J = 8.0 Hz, CH), 9.18 (1 H, d, 3J = 8.6
Hz, CH), 12.01 (1 H, s, OH) ppm.13C NMR (125.7 MHz,
CDCl3): d = 52.5 (OMe), 104.1 (CH), 114.8 (C), 116.8
(CH), 120.6 (CH), 123.1 (C), 124.3 (CH), 127.0 (CH), 127.9
(C), 141.1 (C), 154.2 (COH), 161.4 (CO), 161.5 (CO), 164.1
(CO2) ppm. Anal. Calcd (%) for C14H9NO6 (287.22): C,
58.54; H, 3.16; N, 4.88. Found: C, 58.60; H, 3.14; N, 4.85.
Compound 4g: yellow powder; mp 298–301 °C (dec.); yield
0.58 g (98%). IR (KBr) nmax = 3440, 1764, 1722, 1665, 1621,
1455, 1324, 1286, 1250, 1107, 765 cm–1. 1H NMR (500
MHz, CDCl3): d = 2.32 (3 H, s, Me), 3.78 (3 H, s, OMe),
6.10 (1 H, s, CH), 7.15 (1 H, d, 3J = 8.3 Hz, CH), 7.19 (1 H,
d, 3J = 8.3 Hz), 9.03 (1 H, s, CH), 11.99 (1 H, s, OH) ppm.
13C NMR (125.7 MHz, CDCl3): d = 20.9 (Me), 52.4 (OMe),
104.1 (CH), 114.8 (C), 116.5 (CH), 120.7 (CH), 122.6 (C),
127.4 (CH), 127.9 (C), 133.5 (C), 139.0 (C), 154.3 (C-OH),
161.3 (CO), 161.4 (CO), 164.1 (CO2) ppm. Anal. Calcd (%)
for C15H11NO6 (301.25): C, 59.81; H, 3.68; N, 4.65. Found:
C, 59.80; H, 3.65; N, 4.65.
5
3
X
O
O
X
O
O
– HCl
– HCl
CO2R
O
CO2R
O
N
H
4
N
H
Cl
Cl
Cl
6
7
Scheme 2
In conclusion, we have described a convenient route to
6,10-dioxo-6,10-dihydro-5H-pyrido[1,2-a]quinoxalines and
6,10-dioxo-6,10-dihydropyrido[2,1-c][1,4]benzoxazines
from malonyl dichloride and alkyl 2-[3,4-dihydro-3-oxo-
quinoxaline-2(1H)-ylidene]acetates or alkyl 2-[2-oxo-
2H-benzo[b][1,4]oxazin-3(4H)-ylidene]acetates in CH2Cl2
at room temperature. The advantage of the present proce-
dure is that the reaction is performed in the absence of
added base by simple mixing of the starting materials.
References and Notes
(1) Lindsley, C. W.; Zhao, Z.; Leister, W. H.; Robinson, R. G.;
Barnett, S. F.; Defeo-Jones, D.; Jones, R. E.; Hartman, G. D.;
Huff, J. R.; Huber, H. E.; Duggan, M. E. Bioorg. Med. Chem.
Lett. 2005, 15, 761.
(2) Loriga, M.; Piras, S.; Sanna, P.; Paglietti, G. Farmaco 1997,
52, 157.
(3) Seitz, L. E.; Suling, W. J.; Reynolds, R. C. J. Med. Chem.
2002, 45, 5604.
(4) He, W.; Meyers, M. R.; Hanney, B.; Spada, A.; Blider, G.;
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Perrone, H. Bioorg. Med. Chem. Lett. 2003, 13, 3097.
(5) Kim, Y. B.; Kim, Y. H.; Park, J. Y.; Kim, S. K. Bioorg. Med.
Chem. Lett. 2004, 14, 541.
All other novel compounds isolated possessed spectroscopic
and analytical data in keeping with their proposed structures.
(18) Yavari, I.; Mirzaie, A.; Moradi, L. Helv. Chim. Acta 2006,
89, 2825.
(19) Yavari, I.; Shaabani, A.; Soliemani, H.; Nourmohammadian,
F.; Bijanzadeh, H. Magn. Reson. Chem. 1996, 34, 1003.
(20) Kappe, T.; Linnau, Y.; Stadlbauer, W. Monatsh. Chem.
1977, 108, 103.
(6) Sonawane, N. D.; Rangnekar, D. W. J. Heterocycl. Chem.
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Synlett 2009, No. 12, 1921–1922 © Thieme Stuttgart · New York

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