A clean synthesis of oxazino[5,6-f]quinolinone and naphtho[1,2-e]oxazinone derivatives

Article abstract of DOI:10.1007/s00706-008-0907-3

A clean, simple, one-pot, and efficient synthesis of 1,2-dihydro-1-aryl[1, 3]oxazino[5,6-f]quinolin-3-one and 1,2-dihydro-1-arylnaphtho[1,2-e]-[1,3] oxazine-3-one derivatives was accomplished in good yields via reaction between 6-quinolinol or 2-naphthol, aromatic aldehydes, and methyl carbamate in aqueous medium catalyzed by TEBA (triethylbenzylammonium chloride).

Full text of DOI:10.1007/s00706-008-0907-3

Monatsh Chem 139, 1247–1250 (2008)
DOI 10.1007/s00706-008-0907-3
Printed in The Netherlands
A clean synthesis of oxazino[5,6-f]quinolinone and naphtho[1,2-e]oxazinone
derivatives
Mohammad Hossein Mosslemin, Mohammad Reza Nateghi, Razieh Mohebat
Department of Chemistry, Islamic Azad University, Yazd, Iran
Received 28 October 2007; Accepted 29 January 2008; Published online 11 April 2008
# Springer-Verlag 2008
Abstract A clean, simple, one-pot, and efficient
synthesis of 1,2-dihydro-1-aryl[1,3]oxazino[5,6-f]quin-
olin-3-one and 1,2-dihydro-1-arylnaphtho[1,2-e]-
[1,3]oxazine-3-one derivatives was accomplished in
good yields via reaction between 6-quinolinol or 2-
naphthol, aromatic aldehydes, and methyl carbamate
in aqueous medium catalyzed by TEBA (triethylben-
zylammonium chloride).
view of ideal synthesis [5]. MCRs are perfectly suit-
able for combinatorial library synthesis, and there-
fore finding increasing use in the discovery process
of new drugs and agrochemicals [6].
In this context, ortho-quinone methides (o-QMs)
are highly reactive intermediates, and have been
used in many tandem processes [7, 8]. However,
despite general knowledge of o-QMs for over a cen-
tury, these intermediates still lie outside the syn-
thetic mainstream [9], and only limited work has
appeared regarding their reaction with nucleophiles
[10].
Keywords Quinoline; Oxazinoquinolinone; Naphthoxazi-
none; Triethylbenzylammonium chloride (TEBA).
Considering the above reports, we wish to report
an efficient, one-pot, and three-component method for
the preparation of 1,2-dihydro-1-aryl[1,3]oxazino-
[5,6-f]quinolin-3-one and 1,2-dihydro-1-arylnaphtho-
[1,2-e][1,3]oxazine-3-one derivatives in aqueous
medium.
Introduction
Quinolines and their derivatives have received great
attention because of their wide range of therapeutic
and biological properties [1]. They have emerged
as antimalarial, antiasthmatic, antiinflammatory, an-
tibacterial, antihypertensive, and tyrosine kinase
PDGF-RTK inhibiting agents [2, 3]. Moreover, quin-
olines are valuable synthons, used for assembling
nano and meso structures with enhanced electronic
and photonic properties [4].
One-pot multi-component reactions (MCRs) by
virtue of their convergence, productivity, facile exe-
cution, and generally high yield of products have
attracted considerable attention from the point of
Results and discussion
First, it was found that a mixture of 6-quinolinol
(1a), aromatic aldehyde 2a–2f, and methyl carbamate
(3) in the presence of a catalytic amount of TEBA
(triethylbenzylammonium chloride) at 80ꢀC in water
afforded 1,2-dihydro-1-aryl-[1,3]oxazino[5,6-f]quino-
lin-3-ones 4a–4f in 78–85% yield (Scheme 1).
The optimized results are summarized in Table 1.
Good yields were obtained using aromatic alde-
hydes carrying electron-donating or electron-with-
Correspondence: Mohammad Hossein Mosslemin, Depart-
ment of Chemistry, Islamic Azad University, Yazd
8916871967, Iran. E-mail: mosleminemh@yahoo.com

1248
M. H. Mosslemin et al.
Scheme 1
Table 1 Synthesis of products 4a–4l
Entry
Compound 1
Compound 2
Product 4
Yielda=%
Time=h
1
2
3
4
5
6
7
8
1a
1a
1a
1a
1a
1a
1b
1b
1b
1b
1b
1b
benzaldehyde (2a)
4-chlorobenzaldehyde (2b)
4-fluorobenzaldehyde (2c)
4-bromobenzaldehyde (2d)
4-methoxybenzaldehyde (2e)
4-methylbenzaldehyde (2f)
2a
2b
2c
2d
2e
2f
4a
4b
4c
4d
4e
4f
4g
4h
4i
78
85
82
79
81
80
78
79
81
83
77
81
4
4
4.5
5
6
5
4.5
3.8
3.5
4
5
5.5
9
10
11
12
4j
4k
4l
a
Isolated yields
drawing substituents and problems associated with
toxic solvent use (cost, safety, and pollution) were
avoided.
Under the same conditions, this reaction almost
could not be observed when the aliphatic aldehyde
was used as a starting material. In the absence of
TEBA, the products 4 were obtained in low yields
(<20%) when the reactions were carried out in water
at 80ꢀC. This indicates that a catalyst is requiring for
this reaction.
Scheme 2
1
Encouraged by these results, we carried out the
reaction between 2-naphthol (1b) instead of 6-qui-
nolinol (1a) with aromatic aldehydes 2a–2f and
methyl carbamate (3) in the presence of a catalytic
amount of TEBA at 80ꢀC in water, which also af-
forded 1,2-dihydro-1-arylnaphtho[1,2-e][1,3]oxazine-
3-ones 4g–4l in good yields (Table 1).
Regarding the mechanism of this reaction, it is
noticeable that the reaction of 6-quinolinol (1a),
benzaldehyde (2a), and methyl carbamate (3) under
the same conditions (H2O=TEBA=80ꢀC) after 1 h led
to the formation of the intermediate 5, which was
isolated and characterized by spectroscopic methods
(Experimental section). After 4 h, only compound 4a
was detected by TLC and H NMR. Furthermore,
intermediate 5 in the presence of a catalytic amount
of TEBA at 80ꢀC in water afforded 1,2-dihydro-1-
phenyl[1,3]oxazino[5,6-f]quinolin-3-one (4a) in 70%
yield (Scheme 2).
We have not established an exact mechanism for
the formation of product 4, however, two reasonable
pathways are proposed in Scheme 3. 6-Quinolinol (1a)
or 2-naphthol (1b) first condenses with an aldehyde
to afford o-QMs 6 [10a]. Then methyl carbamate (3)
adds to the o-QMs 6, followed by cyclization affording
the corresponding products 4 and methanol (Pathway
A, Scheme 3). Alternatively, addition of methyl car-
bamate (3) to aldehyde 2 leads to a highly reactive

Oxazino[5,6-f]quinolinone and naphtho[1,2-e]oxazinone derivatives
1249
10cm3 water. Recrystallization from EtOAc:n-hexane (1:3)
afforded the pure product.
1,2-Dihydro-1-phenyl[1,3]oxazino[5,6-f]quinolin-3-one
(4a, C17H12N2O2)
Colorless powder (0.22 g, 78%), mp 243ꢀC (dec); IR (KBr):
ꢀꢀ¼ 3417, 3129, 1743cmꢁ1; MS: m=z (%) ¼ 276 (Mþ, 58),
232 (100); 1H NMR (DMSO-d6): ꢁ ¼ 6.27 (s, CH), 7.30–
8.80 (m, arom), 8.95 (s, NH) ppm; 13C NMR (DMSO-d6):
ꢁ ¼ 53.8, 114.9, 120.9, 122.5, 124.6, 127.3, 128.6, 129.5,
131.6, 132.0, 143.1, 145.6, 147.7, 149.4, 149.8ppm.
1,2-Dihydro-1-(4-chlorophenyl)[1,3]oxazino[5,6-f]quinolin-
3-one (4b, C17H11ClN2O2)
Colorless powder (0.26 g, 85%), mp 209ꢀC (dec); IR (KBr):
ꢀꢀ¼ 3413, 3129, 1741cmꢁ1; MS: m=z (%) ¼ 310 (Mþ, 15),
1
266 (100), 232 (96); H NMR (DMSO-d6): ꢁ ¼ 6.32 (s, CH),
7.31–8.83 (m, arom), 8.97 (s, NH) ppm; 13C NMR (DMSO-
d6): ꢁ ¼ 53.0, 114.4, 120.9, 122.6, 124.5, 129.3, 129.5, 131.8,
131.9, 133.2, 141.9, 145.6, 147.7, 149.3, 149.9ppm.
Scheme 3
1,2-Dihydro-1-(4-flourophenyl)[1,3]oxazino[5,6-f]quinolin-
3-one (4c, C17H11FN2O2)
N-acylimine species 7 [11]. Interception of 7 by qui-
nolinol (1a) or 2-naphthol (1b) and subsequent cycli-
zation affords the corresponding products 4 (Pathway
B, Scheme 3). The TEBA surfactant acts as a phase
transfer agent. It has unique capabilities to enhance
the reaction rate in two-phase reactions [12].
Colorless powder (0.24 g, 82%), mp 205ꢀC (dec); IR (KBr):
ꢀꢀ¼ 3412, 1736cmꢁ1; MS: m=z (%) ¼ 294 (Mþ, 42), 250
(100), 232 (100); 1H NMR (DMSO-d6): ꢁ ¼ 6.31 (s, CH),
7.15–8.82 (m, arom), 8.95 (s, NH) ppm; 13C NMR (DMSO-
d6): ꢁ ¼ 53.0, 114.6, 116.2, 120.9, 122.6, 124.5, 129.5, 131.4,
131.9, 139.3, 145.6, 147.7, 149.3, 149.9, 163.2 ppm.
1,2-Dihydro-1-(4-bromophenyl)[1,3]oxazino[5,6-f]quinolin-
3-one (4d, C17H11BrN2O2)
In conclusion, we have described an efficient,
clean, and one-pot synthesis for the preparation of
1,2-dihydro-1-aryl[1,3]oxazino[5,6-f]quinolin-3-one
and 1,2-dihydro-1-arylnaphtho[1,2-e][1,3]oxazine-
3-one derivatives in three-component cyclo-con-
densation reaction of 6-quinolinol or 2-naphtol,
aromatic aldehydes, and methyl carbamate in aque-
ous media.
Colorless powder (0.28g, 79%), mp 224ꢀC (dec); IR (KBr):
ꢀꢀ¼ 3410, 3134, 1740 cmꢁ1; MS: m=z (%) ¼ 354 (Mþ, 32), 310
(100), 232 (100); 1H NMR (DMSO-d6): ꢁ ¼ 6.27 (s, CH), 7.22–
8.80 (m, arom), 8.96 (s, NH) ppm; 13C NMR (DMSO-d6):
ꢁ ¼ 52.6, 113.84, 120.4, 121.3, 122.1, 123.9, 129.1, 131.3,
131.4, 131.9, 141.8, 145.1, 147.2, 148.8, 149.4ppm.
1,2-Dihydro-1-(4-methoxyphenyl)[1,3]oxazino[5,6-f]-
quinolin-3-one (4e, C18H14N2O3)
Experimental
Colorless powder (0.25 g, 81%), mp 246ꢀC (dec); IR (KBr):
ꢀꢀ¼ 3415, 3128, 1738cmꢁ1; MS: m=z (%) ¼ 306 (Mþ, 37),
262 (100), 232 (100); 1H NMR (DMSO-d6): ꢁ ¼ 3.66 (s,
OCH3), 6.20 (s, CH), 6.85–8.80 (m, arom), 8.89 (s, NH)
ppm; 13C NMR (DMSO-d6): ꢁ ¼ 53.3, 53.5, 114.7, 115.1,
120.9, 122.5, 124.5, 128.6, 131.5, 132.0, 135.2, 145.6, 147.6,
149.4, 149.8, 159.3 ppm.
Melting points were measured on an Electrothermal 9200 ap-
paratus. IR spectra were recorded on a FT-IR 102MB BOMEM
apparatus. Mass spectra were recorded on a FINNIGAN-MAT
8430 mass spectrometer operating at an ionization potential of
70eV. 1H and 13C NMR spectra were recorded on a BRUKER
DRX-300 AVANCE spectrometer at 300.13 and 75.47 MHz.
1H and 13C NMR spectra were obtained on solutions in
DMSO-d6 using TMS.
1,2-Dihydro-1-(4-methylphenyl)[1,3]oxazino[5,6-f]quinolin-
3-one (4f, C18H14N2O2)
Colorless powder (0.23 g, 80%), mp 272ꢀC (dec); IR (KBr):
ꢀꢀ¼ 3445, 3139, 1736cmꢁ1; MS: m=z (%) ¼ 290 (Mþ, 35),
232 (100), 202 (20); 1H NMR (DMSO-d6): ꢁ ¼ 2.21 (s, CH3),
6.22 (s, CH), 7.10-8.79 (m, arom), 8.91 (s, NH) ppm; 13C
NMR (DMSO-d6): ꢁ ¼ 21.0, 53.5, 115.0, 120.9, 122.5, 124.5,
127.3, 129.9, 131.5, 132.0, 137.9, 140.2, 145.6, 147.6, 149.5,
149.8ppm.
General procedure
A mixture of 1 mmol 6-quinolinol or 2-naphtol (1a–1b),
1 mmol aldehyde 2a–2f, 1.5mmol methyl carbamate (3),
and 0.15 g TEBA was suspended in 10 cm3 water, and stirred
at 80ꢀC. The reaction was monitored by TLC. After comple-
tion, the reaction mixture was allowed to cool to room tem-
perature. The solid was collected by filtration and washed with

1250
All the products 4g–4l are known compounds and were
M. H. Mosslemin et al.
References
characterized by IR, NMR, and mass spectroscopic data and
their melting points were compared with reported values
[13].
1. (a) Larsen RD, Corley EG, King AO, Carrol JD, Davis P,
Verhoeven TR, Reider PJ, Labelle M, Gauthier JY, Xiang
YB, Zamboni RJ (1996) J Org Chem 61:3398; (b) Chen
YL, Fang KC, Shen JY, Hsu SL, Tzeng CC (2001) J Med
Chem 44:2374; (c) Roma G, Braccio MD, Grossi G,
Mattioli F, Ghia M (2000) J Med Chem 35:1021
2. (a) Kalluraya B, Sreenivasa S (1998) Farmaco 53:399; (b)
Doube D, Blouin M, Brideau C, Chan C, Desmarais S,
Eithier D, Falgueyret JP, Friesen RW, Girrard M, Girard
Y, Guay J, Tagari P, Young RN (1998) Bioorg Med Chem
Lett 8:1255
1,2-Dihydro-1-phenylnaphtho[1,2-e][1,3]oxazine-3-one
(4g, C18H13NO2)
Colorless powder (0.21 g, 78%), 217–219ꢀC; IR (KBr):
ꢀꢀ¼ 3220, 3145, 1730 cmꢁ1; MS: m=z (%) ¼ 275 (Mþ, 7),
1
231 (100) H NMR (DMSO-d6): ꢁ ¼ 6.20 (s, CH), 7.30–7.96
(m, arom), 8.90 (s, NH) ppm; 13C NMR (DMSO-d6): ꢁ ¼ 54.2,
114.5, 117.3, 123.5, 125.5, 127.4, 127.8, 128.4, 129.1, 129.3,
129.4, 130.7, 130.8, 143.3, 147.8, 149.7ppm.
3. Maguire MP, Sheets KR, McVety K, Spada AP,
Zilberstein A (1994) J Med Chem 37:2129
1,2-Dihydro-1-(4-chlorophenyl)naphtho[1,2-e][1,3]oxazine-
3-one (4h, C18H12ClNO2)
4. (a) Agrawal AK, Jenekhe SA (1991) Macromolcules
24:6806; (b) Zhang X, Shetty AS, Jenekhe SA (2000)
Mocromolecules 33:2064
5. (a) Armstrong RW, Combs AP, Tempest PA, Brown SD,
Keating TA (1996) Acc Chem Rev 29:123; (b) Domling
A (2006) Chem Rev 106:7
6. Domling A, Ugi I (2000) Angew Chem Int Ed 39:3168
7. VanDeWaterRW, PettusTRR(2002)Tetrahedron58:5367
8. Wan P, Backer B, Diao L, Fischer M, Shi Y, Yang C
(1975) Can J Chem 74:465
Colorless powder (0.24 g, 79%), mp 206–209ꢀC; IR
(KBr): ꢀꢀ¼ 3225, 3146, 1736 cmꢁ1; MS: m=z (%) ¼ 309
(Mþ, 9), 231 (100), 202 (27); 1H NMR (DMSO-d6): ꢁ ¼
6.23 (s, CH), 7.31–8.03 (m, arom), 8.89 (s, NH) ppm; 13C
NMR (DMSO-d6): ꢁ ¼ 53.4, 114.1, 117.3, 123.5, 125.6,
127.8, 128.1, 129.1, 129.2, 129.4, 129.4, 130.8, 133.1,
142.2, 147.9, 149.6 ppm.
9. Desimoni G, Tacconi G (1975) Chem Rev 75:651
10. (a) Shaabani A, Rahmati A, Farhangi E (2007) Tetrahe-
dron Lett 48:7291; (b) Angle SR, Rainer JD, Woytowiez
Z (1997) J Org Chem 62:5884; (c) Khodaei MM,
Khosropour AR, Moghanian H (2006) Synlett 916
11. (a) Kappe CO (1997) J Org Chem 62:7201; (b) Huang S,
Pan Y, Zhu Y, Wu A (2005) Org Lett 7:3797; (c) Cristau P,
Vors J, Zhu JP (2003) Tetrahedron Lett 44:5575
12. (a) Jang DO (1996) Tetrahedron Lett 37:5367; (b)
Yorimitsu H, Shinokubo H, Oshima K (2000) Chem Lett
104; (c) Khan TA, Tripoli R, Crawford JJ, Martin CG,
Murphy JA (2003) Org Lett 5:2971
Methyl (6-hydroxquinoline-5-yl)(phenyl)methylcarbamate
(5, C18H16N2O3)
Colorless powder, mp 218ꢀC (dec); IR (KBr): ꢀꢀ¼ 3405, 3198,
1671 cmꢁ1; MS: m=z (%) ¼ 308 (Mþ, 5), 250 (45), 77 (100);
1H NMR (DMSO-d6): ꢁ ¼ 3.35 (s, OCH3), 6.86 (d, J ¼ 8.3 Hz,
CH), 7.13–8.11 (m, arom), 7.93 (d, J ¼ 8.1 Hz, NH), 10.05 (s,
OH) ppm; 13C NMR (DMSO-d6): ꢁ ¼ 50.5, 52.2, 117.9, 119.3,
121.8, 123.4, 126.8, 126.8, 127.5, 128.6, 129.1, 129.5, 131.9,
142.9, 153.8, 157.1ppm.
Acknowledgements
13. (a) Dabiri M, Delbari AS, Bazgir A (2007) Synlett 821;
(b) Dabiri M, Delbari AS, Bazgir A (2007) Heterocycles
71:543
We gratefully acknowledge the financial support from the
Research Council of Islamic Azad University, Yazd Branch.