A three-component, one-pot synthesis of oxazinoquinolin-3-one derivatives

Article abstract of DOI:10.1002/jhet.5570450538

(Chemical Equation Presented) Oxazino[5,6-f]quinolin-3-one derivatives have been synthesized in a one-pot, and efficient process by condensation of 6-quinolinol, aromatic aldehydes and urea under microwave-assisted and thermal solvent-free conditions.

Full text of DOI:10.1002/jhet.5570450538

Sep-Oct 2008
1481
A Three-Component, One-Pot Synthesis of
Oxazinoquinolin-3-one Derivatives
Gazaleh Imani Shakibaei, Hamid Reza Khavasi, Peiman Mirzaei, and Ayoob Bazgir*
Department of Chemistry, Faculty of Science, Shahid Beheshti University, Tehran 1983963113, Iran,
E-mail: a_bazgir@sbu.ac.ir
Received October 16, 2007
H
Solvent-Free/150oC
P-TSA
Ar
N
O
O
OH
ArCHO
+
+
O
or MW/HOAc/4 min.
H2N
NH2
N
N
Oxazino[5,6-f]quinolin-3-one derivatives have been synthesized in a one-pot, and efficient process by
condensation of 6-quinolinol, aromatic aldehydes and urea under microwave-assisted and thermal solvent-
free conditions.
J. Heterocyclic Chem., 45, 1481 (2008).
INTRODUCTION
RESULTS AND DISCUSSION
The quinoline nucleus is the back-bone of many natural
products and pharmacologically significant compounds
displaying a broad range of biological activity [1]. Many
functionalized quinolines are widely used as antimalarial,
antiasthmatic, anti-inflamatory agents, antibacterial,
antihypertensive and tyrosine kinase PDGF-RTK
inhibiting agents [2,3].
To the best of our knowledge, there are no reports in the
literature for the preparation of 1,2-dihydro-1-aryl-
[1,3]oxazino[5,6-f]quinolin-3-one derivatives
4
via
condensation of 6-quinolinol (1), aldehyde 2 and urea (3).
First, in order to find the best conditions for the
synthesis of the quinoline-condensed oxazinone
derivatives, the reaction of 6-quinolinol 1, 4-chloro-
benzaldehyde (2b) and urea (3) was carried out in the
different conditions. As indicated in Table 1, the best
yield was achieved in the presence of p-TSA at 150 °C
under solvent-free conditions (Table 1).
Oxazinone derivatives have received considerable
attention due to the interesting pharmacological properties
associated with this heterocyclic scaffold [4]. For example,
naphthoxazinone derivatives have been reported to act as
antibacterial agents [5], or Efavirenz (Sustiva), a benzoxa-
zinone derivative, is a nonnucleoside reverse transcriptase
inhibitor that has been approved by the FDA in 1998 and is
presently in clinical use for the treatment of AIDS [6].
Therefore, numerous methods for the synthesis of aromatic
oxazinone derivatives exist in the literature [7-10].
Very recently, we reported a novel method for the
synthesis of naphthoxazinone derivatives by the
condensation of ꢀ-naphthol, aldehydes and urea [11]. To
expand this type of tandem process, herein, we utilized 6-
quinolinol (1) to produce novel oxazino[5,6-f]quinolin-3-
one derivatives 4. Therefore, the reaction of 6-quinolinol
(1), aryl aldehyde 2 and urea (3) in the presence of a
catalytic amount of p-toluene sulfonic acid (p-TSA) at
150 °C under solvent-free conditions were examined
(Scheme 1).
Table 1
Condition Effect on the Reaction [a]
Entry
Conditions
Yields %
< 30
1
Solvent-free/120 °C/ p-TSA
2
3
4
5
6
Solvent-free/150 °C/ p-TSA
Solvent-free/170 °C/ p-TSA
Solvent-free/150 °C
77
72
< 20
< 20
< 30
EtOH (Reflux)/ p-TSA
DMF (Reflux)/ p-TSA
[a] 4-Chlorobenzaldehyde (2b) (1 mmol), urea 3 (1.5 mmol), 6-
quinolinol (1) (1 mmol) and Cat. (0.3 mmol), Time= 2.5 h.
Then several aromatic aldehydes 2a-i with 6-quinolinol
(1) and urea (3) under solvent-free conditions using p-
TSA at 150 °C reacted to afford the corresponding
products in good yields (Table 2). High yields were
obtained using aromatic aldehydes carrying electron-
donating or electron-withdrawing substituents.
Under the same conditions, with aliphatic aldehydes the
yields of the reaction notably decreased (i.e., 20%, with
butanal or hexanal), probably due to the possible aldol
condensation side reaction. In the absence of p-TSA, the
Scheme 1
H
Solvent-Free/150oC
P-TSA
Ar
N
O
O
OH
+
+
ArCHO
O
or MW/HOAc/4 min.
H2N
NH2
N
N
1
2a-i
3
4a-i

1482
G. I. Shakibaei, H. R. Khavasi, P. Mirzaei, and A. Bazgi
Vol 45
Table 2
Reaction of 6-Quinolinol 1, aldehydes 2 and urea 3 under solvent-
free (I) and microwave-assisted conditions (II) [a].
2 (Ar =)
Products 4
Yields %/ Time h
Yields %
II
60
I
65/2
77/2.5
60/2
68/2
C6H5 (2a)
4-Cl-C6H4 (2b)
4-F-C6H4 (2c)
4a
4b
4c
4d
4e
4f
75
55
4-Br-C6H4 (2d)
2-Cl-C6H4 (2e)
3-Br-C6H4 (2f)
2-MeO-C6H4 (2g)
4-MeO-C6H4 (2h)
4-Me-C6H4 (2i)
65
58
63/2
71/2
69
60
64
59
4g
4h
4i
66/2
65/2.5
64/2.5
[a] With power of 700 W, time= 4 min.
Figure 1. ORTEP diagram of 4b.
products were obtained in low yields (<20%), when the
reactions were carried out in solvent-free conditions at
150 °C (Table 1, entry 4).
In summary, we have described an efficient one-pot
synthesis for the preparation of 1,2-dihydro-1-aryl-
[1,3]oxazino[5,6-f]quinolin-3-one derivatives 4 in three-
component cyclo-condensation reaction of 6-quinolinol
1, aromatic aldehydes and urea under solvent-free and
microwave-assisted conditions.
In order to decrease the reaction time, microwave
irradiation in the absence or in the presence of different
catalyst such as p-TSA, HOAc, FeCl3, ZnCl2, SnCl2 was
used. In the course of this study it was found that HOAc is
the most effective catalyst in terms of yield. It is clear from
Table 2, using microwave irradiation the reaction time
decreased from 2-2.5 h to 4 min in the presence of catalytic
amount of HOAc. In addition to decrease of reaction time,
the yields in all cases are reasonable (Table 2).
According to the results, and as in numerous classical
multi-component reaction classic [12], the reaction can be
mechanistically considered to proceed through the
acylimine intermediate formed in situ by condensation
reaction of the aldehyde with urea. The subsequent
addition of the 6-quinolinol (1) to the acylimine, followed
by cyclization of the intermediate 5 afforded the
corresponding products 4a-i and ammonia (Scheme 2).
EXPERIMENTAL
Melting points were measured on an Elecrtothermal 9100
apparatus and are uncorrected. Mass spectra were recorded on a
FINNIGAN-MAT 8430 mass spectrometer operating at an
1
ionization potential of 70 eV. H and 13C NMR spectra were
recorded on a BRUKER DRX-300 AVANCE spectrometer at
300.13 and 75.47 MHz, respectively. IR spectra were recorded
using an FTIR apparatus. Elemental analyses were performed
using a Heracus CHN-O-Rapid analyzer. The microwave oven
was a domestic National model NN-6653 with select power
levels. The reflections for X-ray diffraction analysis were
collected on a STOE IPDSII two-circle diffractometer.
General procedure for preparation of 2-dihydro-1-aryl-
[1,3]oxazino[5,6-f]quinolin-3-one under solvent-free condi-
tions (4a-i). A mixture of 6-quinolinol 1 (1 mmol), aldehyde 2
(1 mmol), urea (1.5 mmol) and p-TSA (0.1 g) was heated at 150
°C for appropriative times. After cooling, the reaction mixture
was washed with water and then recrystallized from EtOAc/
Hexane (1:3) to afford the pure product 4-i (Table 2).
Scheme 2
O
O
Ar
Ar-CHO + H2N
NH2
N
NH2
2
3
OH
1
N
General procedure for preparation of 2-dihydro-1-aryl-
[1,3]oxazino[5,6-f]quinolin-3-one under microwave
irradiation (4a-i). A mixture of 6-quinolinol 1 (1 mmol),
aldehyde 2 (1 mmol), urea (1.5 mmol) and HOAc (0.3 mmol)
were finely mixed together. The reaction mixture was placed in
a Pyrex test tube and irradiated for 4 min with a power of 700
W. After cooling, the reaction mixture was washed with water
and then recrystallized from EtOAc/ Hexane (1:3) to afford the
pure product 4a-i (Table 2).
H
O
H
Ar
N
O
Ar
N
-NH3
NH2
OH
O
5
N
N
4
The structures of the products 4a-i were characterized
by ir, 1H nmr, 13C nmr and ms spectra. Finally the
structure of 4b was confirmed by a single-crystal X-ray
analysis (Figure 1) [15].
1,2-Dihydro-1-phenyl-[1,3]oxazino[5,6-f]quinolin-3-one (4a).
1
White powder, mp 242° dec.; ir: 3415, 3129, 1741 cm-1; H nmr
(DMSO-d6): ꢀ 6.26 (1H, s, CH), 7.31-8.81 (10H, m, arom.), 8.94
(1H, s, NH); 13C nmr (DMSO-d6): 53.87, 114.90, 120.92,

Sep-Oct 2008
A Three-Component, One-Pot Synthesis of Oxazinoquinolin-3-one Derivatives
1483
122.56, 124.60, 127.39, 128.62, 129.49, 131.65, 132.01, 143.12,
145.64, 147.76, 149.46, 149.87; ms: m/z 276 (M+, 54), 232
(100). Anal. calcd. For C17H12N2O2: C, 73.90; H, 4.38; N, 10.14.
Found: C, 73.96; H, 4.33; N, 10.17.
1,2-Dihydro-1-(4-methylphenyl)-[1,3]oxazino[5,6-f]quinol-
in-3-one (4i). White powder, mp 270° dec.; ir: 3446, 3138, 1739
cm-1; 1H nmr (DMSO-d6): ꢀ 2.20 (s, 3H, CH3), 6.21 (s,1H, CH),
7.12-8.80 (m, 9H, arom), 8.90 (s, 1H, NH); 13C nmr (DMSO-d6):
ꢀ 21.05, 53.58, 115.01, 120.89, 122.51, 124.57, 127.28, 129.97,
131.53, 132.02, 137.93, 140.25, 145.60, 147.65, 149.47, 149.82;
ms: m/z 290 (M+, 35), 232 (100), 202 (20). Anal. calcd. for
C18H14N2O2: C, 74.47; H, 4.86; N, 9.65. Found: C, 74.39; H,
4.81; N, 9.58.
1,2-Dihydro-1-(4-chlorophenyl)-[1,3]oxazino[5,6-f]quinol-
in-3-one (4b). White powder, mp 210° dec.; ir: 3412, 3128,
1
1739 cm-1; H nmr (DMSO-d6): ꢀ 6.31 (s, 1H, CH), 7.31-8.82
(m, 9H, arom), 8.99 (s, 1H, NH); 13C nmr (DMSO-d6) : ꢀ 53.07,
114.40, 120.98, 122.68, 124.51, 129.36, 129.52, 131.84, 131.96,
133.23, 141.97, 145.62, 147.79, 149.31, 149.98; ms: m/z 310
(M+, 15), 266 (100), 232 (96). Anal. calcd. for C17H11ClN2O2: C,
65.71; H, 3.57; N, 9.02. Found: C, 65.77; H, 3.61; N, 9.09.
1,2-Dihydro-1-(4-flourophenyl)-[1,3]oxazino[5,6-f]quinol-
in-3-one (4c). White powder, mp 203° dec.; ir: 3413, 1737 cm-1;
1H nmr (DMSO-d6): ꢀ 6.31 (s, 1H, CH), 7.16-8.81 (m, 9H,
arom), 8.97 (s, 1H, NH); 13C nmr (DMSO-d6) : ꢀ 53.02, 114.68,
116.23, 120.97, 122.63, 124.51, 129.57, 131.46, 131.97, 139.37,
145.64, 147.73, 149.35, 149.94, 163.28; ms: m/z 294 (M+, 42),
250 (100), 232 (100). Anal. calcd. for C17H11FN2O2: C, 69.38;
H, 3.77; N, 9.52. Found: C, 69.31; H, 3.71; N, 9.57.
Acknowledgments. We gratefully acknowledge the financial
support from the Research Council of Shahid Beheshti
University.
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in-3-one (4d). White powder, mp 226° dec.; ir: 3413, 3135,
1
1740 cm-1; H nmr (DMSO-d6): ꢀ 6.28 (s, 1H, CH), 7.24-8.80
(m, 9H, arom), 8.97 (s, 1H, NH); 13C nmr (DMSO-d6): ꢀ 52.63,
113.84, 120.48, 121.33, 122.19, 123.99, 129.17, 131.34, 131.46,
131.96, 141.87, 145.11, 147.28, 148.81, 149.48; ms: m/z 354
(M+, 32), 310 (100), 232 (100). Anal. calcd. for C17H11BrN2O2:
C, 57.49; H, 3.12; N, 7.89. Found: C, 57.41; H, 3.07; N, 7.82.
1,2-Dihydro-1-(2-chlorophenyl)-[1,3]oxazino[5,6-f]quinol-
in-3-one (4e). White powder, mp 271° dec.; ir: 3422, 3113, 1737
cm-1; 1H nmr (DMSO-d6): ꢀ 6.57 (s, 1H, CH), 7.30-8.80 (m, 9H,
arom), 8.94 (s, 1H, NH); 13C nmr (DMSO-d6): ꢀ 52.29, 113.01,
120.92, 122.72, 124.52, 128.83, 130.71, 131.23, 132.04, 132.17,
139.62, 145.64, 148.18, 148.77, 149.84; ms: m/z 310 (M+, 10),
266 (20), 232 (100). Anal. calcd. for C17H11ClN2O2: C, 65.71; H,
3.57; N, 9.02. Found: C, 65.72; H, 3.60; N, 9.10.
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1,2-Dihydro-1-(3-bromophenyl)-[1,3]oxazino[5,6-f]quinol-
in-3-one (4f). White powder, mp 274° dec.; ir: 3452, 3112, 1741
cm-1; 1H nmr (DMSO-d6): ꢀ 6.32 (s, 1H, CH), 7.24-8.84 (m, 9H,
arom), 8.99 (s, 1H, NH); 13C nmr (DMSO-d6): ꢀ 53.15, 114.12,
120.99, 122.53, 122.76, 124.52, 126.27, 130.40, 131.58, 131.89,
131.94, 145.53, 145.63, 147.91, 149.28, 150.03; ms: m/z 354
(M+, 7), 312 (18), 232 (100). Anal. calcd. for C17H11BrN2O2: C,
57.49; H, 3.12; N, 7.89. Found: C, 57.84; H, 3.15; N, 7.80.
1,2-Dihydro-1-(2-methoxyphenyl)-[1,3]oxazino[5,6-f]quin-
olin-3-one (4g). White powder, mp 264° dec.; ir: 3440, 3127,
1732 cm-1; 1H nmr (DMSO-d6): ꢀ 3.77 (s, 3H, OCH3), 6.36 (s,
1H, CH), 6.87-8.58 (m, 9H, arom), 8.78 (s, 1H, NH); 13C nmr
(DMSO-d6): ꢀ 50.58, 56.05, 112.46, 113.79, 120.72, 121.20,
122.45, 124.75, 129.33, 130.24, 130.47, 131.30, 131.60, 145.49,
148.02, 149.55, 149.67, 157.01; ms: m/z 306 (M+, 13), 248 (21),
232 (100). Anal. calcd. for C17H14N2O3: C, 70.58; H, 4.61; N,
9.15. Found: C, 70.51; H, 4.65; N, 9.09.
1,2-Dihydro-1-(4-methoxyphenyl)-[1,3]oxazino[5,6-f]quin-
olin-3-one (4h). White powder, mp 249° dec.; ir: 3413, 3128,
1740 cm-1; 1H nmr (DMSO-d6): ꢀ 3.67 (s, 3H, OCH3), 6.22 (s,
1H, CH), 6.86-8.81 (m, 9H, arom), 8.89 (s, 1H, NH); 13C nmr
(DMSO-d6): ꢀ 53.29, 53.53, 114.76, 115.14, 120.91, 122.51,
124.57, 128.66, 131.51, 132.06, 135.29, 145.64, 147.61, 149.48,
149.83, 159.37; ms: m/z 306 (M+, 37), 262 (100), 232 (100).
Anal. calcd. for C18H14N2O3: C, 70.58; H, 4.61; N, 9.15. Found:
C, 70.64; H, 4.61; N, 9.21.
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[13] Crystal data analyses: Stoe IPDS-II two-circle
diffractometer, MoKꢁ radiation (ꢂ = 0.71073); T =293(2) K; Graphite
monochromator; numerical absorption correction. Structure solution
by direct methods using SHELXS and refinement by full-matrix least-
squares on F2 using SHELXL of the X-STEP32 suite of programs [14]
all non-hydrogen atoms were refined anisotropically. Crystal data for
4b: C17H11ClN2O2.(CH3)2SO, M = 387.86 gmol-1; crystal dimensions
0.30 x 0.25 x 0.20 mm3; Triclinic, space group Pꢃ, Z=2; a =
8.7331(17), b = 9.1208(18), c = 13.834(3) Å, ꢁ = 72.82(3)°, ꢄ =
89.37(3)°, ꢅ = 64.76(3)°; V = 943.8(3) Å3; F(000) = 402, ꢆcalc = 1.365
g cm-3; 2.57°< <29.32°; section of the reciprocal lattice: -9 ꢀ h ꢀ 12, -
12 ꢀ k ꢀ 12, -16 ꢀ l ꢀ 18; of 10725 measured reflections, 5066 were
independent (Rint=0.0965) and 5066 with
I > 2ꢇ(I); absorption
coefficient 0.334 mm-1; R1 = 0.1048 for I > 2ꢇ(I), wR2 = 0.2088 (all
data) and S = 1.115; largest peak (0.807 eÅ-3) and hole (-0.518 eÅ-3).
Crystallographic data for 4b have been deposited with the Cambridge

1484
G. I. Shakibaei, H. R. Khavasi, P. Mirzaei, and A. Bazgi
Vol 45
Crystallographic Data Centre. Copies of the data can be obtained, free
of charge, on application to The Director, CCDC 664117, Union Road,
Cambridge CB2 1EZ, UK. Fax: +44 1223 336033 or e-mail:
deposit@ccdc.cam.ac.uk.
[14] X-STEP32 Version 1.07b, X-ray structure evaluation
package, 2000, Stoe & Cie, Darm-stadt, Germany.