A novel three-component, one-pot synthesis of 1,2-dihydro-1-aryl-naphtho[1, 2-e][1,3]oxazine-3-one derivatives under microwave-assisted and thermal solvent-free conditions

Article abstract of DOI:10.1055/s-2007-970763

1,2-Dihydro-1-arylnaphtho[1,2-e][1,3]oxazine-3-one derivatives were synthesized in moderate to high yields using a novel, facile, and one-pot condensation of β-naphthol, aromatic aldehydes and urea under microwave-assisted and thermal solvent-free conditi

Full text of DOI:10.1055/s-2007-970763

LETTER
821
A Novel Three-Component, One-Pot Synthesis of 1,2-Dihydro-1-aryl-
naphtho[1,2-e][1,3]oxazine-3-one Derivatives under Microwave-Assisted
and Thermal Solvent-Free Conditions
A
N
ovel Three-Compo
i
nent,
O
n
ne-Pot
S
ynt
o
hesis of 1,2-D
o
ihydro-1-arylnaph
D
tho[1,2-
e
]
[1,3]oxa
a
zine-3-one
b
D
erivatives iri, Akram Sadat Delbari, Ayoob Bazgir*
Department of Chemistry, Shahid Beheshti University, P. O. Box 19396-4716, Tehran, Iran
E-mail: a_bazgir@sbu.ac.ir
Received 11 September 2006
Multicomponent reactions (MCRs) constitute an especial-
ly attractive synthetic strategy due to the fact that the
products are formed in a single step and diversity can be
achieved simply by varying the reacting components.8
Abstract: 1,2-Dihydro-1-arylnaphtho[1,2-e][1,3]oxazine-3-one
derivatives were synthesized in moderate to high yields using a
novel, facile, and one-pot condensation of b-naphthol, aromatic
aldehydes and urea under microwave-assisted and thermal solvent-
free conditions.
In continuation of our previous work on the synthesis of
heterocyclic compounds9 and MCRs,10 we wish to re-
port a novel, efficient, one-pot, three-component method
for the preparation of 1,2-dihydro-1-arylnaphtho[1,2-
e][1,3]oxazin-3-one derivatives under thermal as well as
microwave-assisted, solvent-free conditions.
Key words: naphthoxazinone, microwave, solvent-free, naphthol,
multi-component
Aromatic-condensed oxazinone derivatives are an impor-
tant class of heterocyclic compounds, since many of these
heterocyclic systems exhibit biological activities.1 For ex-
ample, naphthalene-condensed 1,3-oxazin-3-ones have
been reported to act as antibacterial agents.2 This class of
compound has also been used as precursors in the prepa-
ration of phosphinic ligands for asymmetric catalysis.3
However, to the best of our knowledge, there have only
been a few reports of the synthesis of naphthalene-con-
densed oxazinone derivatives in the literature.2,4 Recently,
Fulop et al. disclosed that the condensation of amino
alkylnaphthols as precursors with phosgene in the pres-
ence of triethylamine, gives naphthalene-condensed 1,3-
oxazin-3-one derivatives in moderate yields.5 Cimarelli
and co-workers used carbonyl diimidazole instead of
phosgene for the synthesis of these compounds.6
After preliminary experimentation, it was found that a
mixture of b-naphthol (1), benzaldehyde (2a) and urea 3
in the presence of a catalytic amount of p-toluenesulfonic
acid (PTSA) at 160 °C for 1.5 hours under solvent-free
conditions afforded 1,2-dihydro-1-phenylnaphtho[1,2-
e][1,3]oxazine-3-one (4a) in 58% yield (Scheme 1).11
In order to find the best catalyst for the synthesis of the
naphthalene-condensed oxazinone derivatives, the reac-
tion of b-naphthol, benzaldehyde and urea was carried out
either in the absence of catalyst or in the presence of var-
ious protic or Lewis acids under similar conditions
(Table 1). As shown, the best yield was achieved when
PTSA was used (Table 1, entry 2).
Encouraged by this success, we attempted the reaction of
b-naphthol with a range of other aromatic aldehydes 2b–
g and urea under similar conditions (using PTSA), fur-
nishing the respective naphthoxazinone 4b–g in good
yields. The optimized results are summarized in Table 2.
The thermal solvent-free conditions are well suited for
either electron-donating or electron-withdrawing sub-
stituents on the aromatic aldehydes.
In all these methods either expensive reagents or solvents
are required or the reagents used are toxic and hazardous.
Furthermore, for the preparation of starting materials such
as amino alkylnaphthol, a multi-step reaction using harsh
conditions is needed.7 Therefore, discovery of new, sim-
ple, green and one-pot methods for the synthesis of naph-
thoxazinone derivatives is of prime interest.
CHO
H
Ar
N
O
O
solvent-free, 160 °C
PTSA, 1.5 h
OH
+
+
O
H2N
NH2
or MW, 6 min
X
2a–g
3
4a–g
Scheme 1
SYNLETT 2007, No. 5, pp 0821–0823
1
6.
0
3.
2
0
0
7
Advanced online publication: 08.03.2007
DOI: 10.1055/s-2007-970763; Art ID: D27006ST
© Georg Thieme Verlag Stuttgart · New York

822
M. Dabiri et al.
LETTER
Table 1 Catalyst Effect on Reactiona
H
O
H
Ph
N
O
Ph
N
NH2
OH
Entry
Catalyst
AcOH
PTSA
LiCl
Yields (%)b
O
MW, 6 min
1
2
3
4
5
6
45
58
38
30
–
4a
5
Scheme 2
CuCl2
NiCl2
–
According to these results, the reaction can be mechanis-
tically considered to proceed through the acylimine inter-
mediate (formed in situ by reaction of the aldehyde with
urea).13 The subsequent addition of the b-naphthol to the
acylimine, followed by cyclization affords the corre-
sponding products 4a–g and ammonia (Scheme 3). The
35
a Benzaldehyde (1 mmol), urea (1.5 mmol), b-naphthol (1 mmol),
catalyst (0.3 mmol).
b Isolated yields.
1
structures of the products were characterized by IR, H
NMR, C NMR and MS spectra.14 Replacement of urea
13
with N-methyl urea also afforded product 4a in high yield.
However, replacement of urea with N,N¢-dimethyl urea
gave no product (Scheme 4). All starting materials were
recovered indicating that the presence of an unsubstituted
amino group is necessary for production of the key
acylimine intermediate.
Table 2 Reaction of b-Naphthol with Aldehydes and Urea under
Solvent-Free (I) and Microwave-Assisteda (II) Conditions
Product 4 Ar
Yield (%)b
I
Mp (°C)
II
a
b
c
d
e
f
Ph
58
60
59
63
61
63
64
81
79
73
69
77
80
82
218–220
166–168
185–188
180 (dec.)
202–204
208–210
220–223
O
O
Ar
4-MeC6H4
4-MeOC6H4
4-HOC6H4
4-FC6H4
4-ClC6H4
4-BrC6H4
H2N
NH2
N
NH2
ArCHO +
OH
O
H
N
H
Ar
O
Ar
N
– NH3
NH2
O
OH
g
4
5
a With a power of 900 W.
b Isolated yields.
Scheme 3
O
In order to decrease the reaction time, microwave irra-
diation under solvent-free conditions was used.12 The
reaction time decreased from 1.5 hours to 6 minutes.
Moreover, the yields of products increased in all cases that
were examined (Table 2). Interestingly, all reactions un-
der microwave-assisted conditions proceeded without the
use of any acidic catalyst, which is another advantage of
this method in the synthesis of this class of compound.
H
H2N
NHMe
NHMe
Ar
N
O
CHO
OH
+
MW,
6 min
O
O
MeHN
no reaction
Scheme 4
On investigating the reaction mechanism, it was noticed
that when b-naphthol, benzaldehyde and urea were irradi-
ated for one minute, the reaction led to the formation of
the intermediate 5. This intermediate was isolated and
characterized by spectroscopic methods. However, exten-
sion of reaction time to three minutes led to a mixture of
4a and intermediate 5 (monitored by TLC and 1H NMR).
After six minutes, only compound 4a was detected by
TLC and 1H NMR. Furthermore, when intermediate 5 was
isolated and exposed to microwave irradiation, the prod-
uct 4a was obtained in good yield (Scheme 2).
In addition, replacement of b-naphthol with a-naphthol
under both conditions produced no product.
In conclusion, we have described a novel, efficient and
one-pot synthesis for the preparation of naphthoxazine-3-
one derivatives in three-component cyclo-condensation
reactions of b-naphthol, aromatic aldehydes and urea un-
der thermal solvent-free conditions or microwave irradia-
tion. The novelty and synthetic utility of this methodology
was demonstrated in the efficient synthesis of naphthox-
azinone derivatives.
Synlett 2007, No. 5, 821–823 © Thieme Stuttgart · New York

LETTER
A Novel Three-Component Synthesis
823
(12) Typical procedure under microwave-assisted conditions:
A mixture of b-naphthol (1 mmol), benzaldehyde (1 mmol)
and urea (1.5 mmol) were finely mixed together. The
reaction mixture was placed in a screw-capped vial and
irradiated for 6 min with a power of 900 W. After cooling,
the reaction mixture was washed with H2O and then
recrystallized from EtOAc–hexane (1:3) to afford the pure
product 4a (81%); mp 218–220 °C; IR (KBr): 3295, 1730,
1517 cm–1; 1H NMR (300 MHz, DMSO-d6): d = 6.19 (d,
J = 2.1 Hz, 1 H, CH), 7.24–8.00 (m, 11 H, Ar–H), 8.87 (br s,
1 H, NH); 13C NMR (75 MHz, DMSO-d6): d = 54.20,
114.50, 117.32, 123.57, 125.54, 127.42, 127.81, 128.47,
129.08, 129.32, 129.41, 130.68, 130.86, 143.34, 147.85,
149.77; MS (ESI): m/z (%) = 275 (7) [M+], 231 (100), 202
(35), 51 (24).
Acknowledgment
We gratefully acknowledge the financial support from the Research
Council of Shahid Beheshti University.
References and Notes
(1) (a) Patel, M.; McHugh, R. J. Jr.; Cordova, B. C.; Klabe, R.
M.; Erickson-Viitanen, S.; Trainor, G. L.; Ko, S. S. Bioorg.
Med. Chem. Lett. 1999, 9, 3221. (b) El-Shafei, H. A.; Badr-
Eldin, S. M. Egypt. J. Microbiol. 1994, 27, 353.
(c) Sugimoto, H.; Yonaga, M.; Karibe, N.; Limura, Y.;
Nagato, S.; Sasaki, A.; Yamanishi, Y.; Ogura, H.; Kosasa,
T.; Uchikoshi, K.; Yamatsu, K. Eur. Patent Appl. Ep 468
187, 1992; Chem. Abstr. 1992, 116, 235643. (d) Waxman,
L.; Darke, P. L. Antiviral Chem. Chemother. 2000, 11, 1.
(e) Girgis, A. S. Pharmazie 2000, 466.
(2) Latif, N.; Mishriky, N.; Assad, F. M. Aust. J. Chem. 1982,
35, 1037.
(3) Wang, Y.; Li, X.; Ding, K. Tetrahedron: Asymmetry 2002,
13, 1291.
(4) Ikeda, K.; Morimoto, T.; Sekia, M. Chem. Pharm. Bull.
1980, 1178.
(5) Szatmari, I.; Hetenyi, A.; Lazar, L.; Fulop, F. J. Heterocyclic
Chem. 2004, 41, 367.
(6) Cimarelli, C.; Palmieri, G.; Volpini, E. Can. J. Chem. 2004,
82, 1314.
(7) (a) Betti, M. Gazz. Chim. Ital. 1900, 30II, 310. (b) Betti, M.
Org. Synth., Coll. Vol. I 1941, 381.
(8) (a) Domling, A.; Ugi, I. Angew. Chem. Int. Ed. 2000, 39,
3168. (b) Ugi, I.; Domling, A. Endeavour 1994, 18, 115.
(c) Heck, S.; Domling, A. Synlett 2000, 424.
(9) (a) Shaabani, A.; Bazgir, A. Tetrahedron Lett. 2004, 45,
2575. (b) Shaabani, A.; Dabiri, M.; Bazgir, A. Dyes Pigm.
2006, 71, 68. (c) Bazgir, A. J. Chem. Res., Synop. 2006, 1.
(d) Shaabani, A.; Bazgir, A.; Teimouri, F. Tetrahedron Lett.
2003, 44, 857.
(10) (a) Shaabani, A.; Bazgir, A. Mol. Div. 2004, 8, 141.
(b) Shaabani, A.; Teimouri, M. B.; Bazgir, A.; Bijanzadeh,
H. R. Mol. Div. 2003, 6, 199. (c) Mohammad Pour-Amini,
M.; Shaabani, A.; Bazgir, A. Catal. Commun. 2006, 7, 843.
(11) Typical procedure for the preparation of 1,2-dihydro-1-
phenylnaphtho[1,2-e][1,3]oxazine-3-one (4a) under
thermal solvent-free conditions: A mixture of b-naphthol
(1 mmol), benzaldehyde (1 mmol), urea (1.5 mmol) and
PTSA (0.3 mmol) was finely mixed together. The reaction
mixture was placed in a screw-capped vial and heated at
160 °C for 1.5 h. After cooling, the reaction mixture was
washed with H2O and then recrystallized from EtOAc–
hexane (1:3) to afford the pure product 4a as a white powder
(58%).
(13) (a) Kappe, C. O. J. Org. Chem. 1997, 62, 7201. (b) Huang,
S.; Pan, Y.; Zhu, Y.; Wu, A. Org. Lett. 2005, 7, 3797.
(c) Cristau, P.; Vors, J.; Zhu, J. P. Tetrahedron Lett. 2003,
44, 5575. (d) Dondoni, A.; Massi, A.; Minghini, E.;
Bertolasi, V. Tetrahedron 2004, 60, 2311.
(14) Selected characterization data:
1,2-Dihydro-1-(4-methylphenyl)naphtho[1,2-
e][1,3]oxazine-3-one (4b): mp 166–16 °C; IR (KBr): 3230,
3139, 1717 cm–1; 1H NMR (300 MHz, DMSO-d6): d = 2.21
(s, 3 H, CH3), 6.13 (d, J = 2.4 Hz, 1 H, CH), 7.10–7.99 (m,
10 H, Ar–H), 8.81 (s, 1 H, NH); 13C NMR (75 MHz, DMSO-
d6): d = 21.06, 53.98, 114.61, 117.29, 123.56, 125.49,
127.32, 127.76, 129.05, 129.33, 129.89, 130.59, 130.85,
137.78, 140.43, 147.80, 149.81; MS (ESI): m/z (%) = 290
(10) [M+ + H], 231 (100), 202 (20).
1,2-Dihydro-1-(4-chlorophenyl)naphtho[1,2-
e][1,3]oxazine-3-one (4f): mp 208–210 °C; IR (KBr): 3224,
3146, 1734 cm–1; 1H NMR (300 MHz, DMSO-d6): d = 6.24
(s, 1 H, CH), 7.31–8.01 (m, 10 H, Ar–H), 8.91 (s, 1 H, NH);
13C NMR (75 MHz, DMSO-d6): d = 53.42, 114.02, 117.34,
123.50, 125.62, 127.91, 128.06, 129.13, 129.23, 129.37,
129.42, 130.87, 133.06, 142.22, 147.90, 149.61; MS (ESI):
m/z (%) = 309 (5) [M+], 265 (60), 231 (100), 202 (27), 115
(15).
1-{[2-Hydroxynaphthalen-1-yl](phenyl) methyl} urea
(intermediate 5): mp 190–192 °C; IR (KBr): 3463, 3406,
3347, 3219, 1664 cm–1; 1H NMR (300 MHz, CD3SOCD3):
d = 5.82 (s, 2 H, NH2, exchanges with D2O), 6.91–7.81 (m,
13 H), 9.94 (br s, 1 H, OH); 13C NMR (75 MHz,
CD3SOCD3): d = 48.56, 119.05, 120.58, 122.72, 123.27,
126.22, 126.81, 128.26, 128.69, 129.0, 129.33, 132.71,
144.77, 153.51, 159.01; MS (ESI): m/z (%): 275 (5) [M+ –
NH3], 231 (100), 202 (15), 144 (100).
Synlett 2007, No. 5, 821–823 © Thieme Stuttgart · New York

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