Synthesis of 1,2-dihydro-1-arylnaphtho[1,2-e][1,3]oxazine-3-one catalyzed by pyridinium-based ionic liquid

Article abstract of DOI:10.1007/s11164-012-0776-6

Some pyridinium-based functionalized ionic liquids have been used as novel catalysts for the synthesis of 1,2-dihydro-1-arylnaphtho[1,2-e][1,3]oxazine-3- one derivatives via the one-pot multi-component condensation of β-naphthol, aromatic aldehydes, and u

Full text of DOI:10.1007/s11164-012-0776-6

Res Chem Intermed (2013) 39:2505–2512
DOI 10.1007/s11164-012-0776-6
Synthesis of 1,2-dihydro-1-arylnaphtho[1,2-e]
[1,3]oxazine-3-one catalyzed by pyridinium-based
ionic liquid
•
Fang Dong Yang Li-fang Yang Jin-ming
•
Received: 29 July 2012 / Accepted: 17 August 2012 / Published online: 1 September 2012
Ó Springer Science+Business Media B.V. 2012
Abstract Some pyridinium-based functionalized ionic liquids have been used as novel
catalysts for the synthesis of 1,2-dihydro-1-arylnaphtho[1,2-e][1,3]oxazine-3-one
derivatives via the one-pot multi-component condensation of b-naphthol, aromatic
aldehydes, and urea under solvent-free conditions, to afford good to excellent yields
ranging from 76 to 91 % within 60 min. A possible mechanism to account for the
reaction is proposed.
Keywords Naphthoxazinone Á Synthesis Á Pyridinium-based ionic liquid Á
Solvent-free Á Multi-component reaction
Introduction
One-pot multi-component reactions (MCRs) have gained wide applicability in the
field of synthetic organic chemistry, as they increase the efficiency of the reaction
and decrease the number of laboratory operations, along with quantities of solvents
and chemicals used. Since they are performed without the need to isolate any
intermediate, the process reduces the reaction time and saves both energy and raw
materials. Therefore, the design of novel MCRs has attracted a great deal of
attention from research groups working in the field of medicinal chemistry, drug
discovery, and materials science [1–5].
Aromatic-condensed oxazinone derivatives are an important class of heterocyclic
compounds studied, because many of these heterocyclic systems exhibit biological
activities as potential antimicrobial agents, anti-inflammatory, acetylcholinesterase
inhibitor, analgesics, bactericides, and muscle relaxants [6–8].
F. Dong (&) Á Y. Li-fang Á Y. Jin-ming
Department of Pharmaceutical Engineering, Yancheng Normal University, 50 Kai Fang Da Dao,
Yancheng 224002, Jiangsu, People’s Republic of China
e-mail: fangdong106@sina.com
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F. Dong et al.
Several synthetic methods for benzoxazinones have been reported in the
literature; however, very few were concerned with the synthesis of naphthalene-
condensed oxazinone derivatives reported in the literature. Szatmari et al. [9]
reported the syntheses of naphthalene-condensed 1,3-oxazin-3-ones derivatives by
condensation of amino alkylnaphthols as precursors with phosgene in the presence
of triethylamine, Cimarelli et al. [10] synthesized these compounds using carbonyl
diimidazole instead of phosgene. Bazgir and co-workers [11] reported a one-pot
synthesis of naphthoxazinone derivatives with the same reactants under the
irradiation of MW. Recently, Mahdavinia and co-authors [12] reported the solvent-
free synthesis of similar naphthoxazinone in the presence of perchloric acid
supported on silica. Therefore, the development of novel, simple, and green
methods for the synthesis of naphthoxazinone derivatives are of great importance.
In recent years, ionic liquids have attracted increasing attention due to their
particular properties, such as negligible vapor pressure, wide liquid range, high
thermal stability, and making them a greener alternative to volatile organic solvents.
In addition, Brønsted acidic task-specific ionic liquids (TSILs) have a dual role
(solvent and catalyst) in multi-component reactions [13–18] to afford higher yields
and selectivity against traditional acid catalysts. In fact, the use of Brønsted acidic
TSILs as catalysts is an area of ongoing activity, and it is currently a hot area for the
development and exploration of TSILs in multi-component.
In continuation of our work on clean MCRs, and considering the importance of
ionic liquid catalytic systems [19, 20], we synthesized some pyridinium-based
functionalized ionic liquids (Py-FILs) including N-propanesulfonic acid pyridinium-
hydrogen sulfate ([PSPy][HSO4]), N-propanesulfonic acid hexafluorophosphate
([PyPS][PF6]), N-propanesulfonic acid tetrafluoroborate ([PyPS][BF4]), N-propane-
sulfonic acid p-toluenesulfonate ([PyPS]p-TSA), and N-propanesulfonic acid dihy-
drogen phosphate ([PyPS][H2PO4]) (Fig. 1). These ionic liquids were investigated to
catalyze for the synthesis of 1,2-dihydro-1-arylnaphtho[1,2-e][1,3]oxazine.
Results and discussion
In the initial study, the reaction of 2-naphthol, benzaldehyde and urea was selected
as the model. We screened some pyridinium-based ionic liquids with different
anions for their ability to catalyze the model reaction under different thermal
conditions. A variety of them, such as [PSPy][HSO4], [PyPS][H2PO4], [PyPS]p-
TSA, [PyPS][BF4], and [PyPS][PF6], were investigated for comparison.
We found that [PyPS][H2PO4] and [PyPS]p-TSA have relatively lower catalytic
activity for this model reaction, while [PyPS][HSO4], [PyPS][BF4], and
[PyPS][PF6] have relatively higher yields. But [PyPS][BF4] and [PyPS][PF6] began
to decompose at high temperature for a long time. Furthermore, the procedures for
the preparation of [PyPS][HSO4] are easier than for [PyPS][BF4] and [PyPS][PF6].
Additionally, [PyPS][HSO4] is a halogen-free ionic liquid, which might be more
eco-friendly and less expensive. As the precursor of [PyPS][HSO4], PPS is
commercially available as a relatively inexpensive brightening agent for bath elec-
troplating. The material of [PyPS][HSO4] is less expensive than imidazolium-based
123

Synthesis of 1,2-dihydro-1-arylnaphtho[1,2-e][1,3]oxazine-3-one catalyzed
2507
BF4
PF6
HSO4
N
SO3H
N
SO3H
N
SO3H
[PSPy][BF4]
[PSPy][PF6]
[PSPy][HSO4]
H2PO4
p-TSA
N
SO3H
N
[PSPy][p-TSA]
Fig. 1 Structures of the Py-FILs
SO3H
[PSPy][H2PO4]
ionic liquids. Herein, [PyPS][HSO4] was selected and the results are summarized in
Table 1. It worth noting that the reaction temperature for synthesis of naphthox-
azinone should be above 150 °C, as only amidoalkyl naphthols were isolated and
detected when the reaction temperature was lower than 120 °C (Table 1, entry 8).
After the selection of catalyst, the optimal amount of [PyPS][HSO4] for the
model reaction was subsequently explored, and the results are summarized in
Table 2. In the absence of catalysts, no product was obtained even after 5 h. Good
or excellent yields could be obtained with 10 mol% catalyst (entry 4). No significant
impact was found on the yields when the amount of catalyst increased from 10 to
20 % mol. Thus, 10 mol% was chosen as the optimal dosage of [PyPS][HSO4].
To optimize the reaction conditions, different polar solvents were then selected as
the reaction medium. The results are summarized in Table 3. Among the six
reaction conditions, all were accomplished successfully, but only a solvent-free
condition could be considered the optimal procedure. Considering the reaction rate
and yield, solvent-free condition was confirmed to be the best, especially because, in
addition, it is an eco-friendly and economic procedure under solvent-free
conditions.
With the experiment data above to hand, a Ritter-type reaction with various
aldehydes was then explored under the above optimized reaction conditions
(Scheme 1), and the results are presented in Table 4. It can be easily seen that this
Table 1 Catalytic
performance in the model
Entry Catalytic system T (°C) Time (min) Isolated yield (%)
reaction of naphthol,
benzaldehyde and urea
1
2
3
4
5
6
7
8
[PyPS][H2PO4]
[PyPS]p-TSA
[PyPS][PF6]
150
150
150
150
150
160
150
120
60
60
60
60
60
60
90
20
56
60
68
73
85
85
85
95a
[PyPS][BF4]
Reaction conditions: naphthol
(2.5 mmol), benzaldehyde
(2.5 mmol), urea (3.5 mmol),
ionic liquids (0.25 mmol)
[PyPS][HSO4]
[PyPS][HSO4]
[PyPS][HSO4]
[PyPS][HSO4]
a
Amidoalkyl naphthols were
produced
123

2508
F. Dong et al.
Table 2 Influence of the
catalytic amounts of
[PyPS][HSO4] on the model
reaction
Entry
Catalytic system
Catalytic
amounts (mol%)
Time
(min)
Isolated
yield (%)
1
2
3
4
5
6
[PyPS][HSO4]
[PyPS][HSO4]
[PyPS][HSO4]
[PyPS][HSO4]
[PyPS][HSO4]
[PyPS][HSO4]
3
5
60
60
60
60
60
60
62
68
77
85
86
86
8
10
15
20
Reaction conditions: naphthol
(2.5 mmol), benzaldehyde
(2.5 mmol), urea (3.5 mmol),
150 °C
Table 3 [PyPS][HSO4]-
catalyzed model reaction in
different solvents at reflux
conditions
Entry
Solvent
Time (min)
Isolated
yield (%)
1
2
3
4
5
6
Solvent-free
DMF
60
120
120
120
120
120
85a
16
0
Ethanol
Reaction conditions: naphthol
(2.5 mmol), benzaldehyde
(2.5 mmol), urea (3.5 mmol)
Acetonitrile
0
Dichloromethane
Water
0
0
a
150 °C
one-pot, three-component condensation reaction was completed successfully. In the
case of optimal conditions, aromatic aldehydes with electron-donation or weak
electron-withdrawing substituents could afford reasonable or good yields of 1,2-
dihydro-1-arylnaphtho[1,2-e][1,3]oxazine; however, almost no product 4 could be
detected for strong electron-withdrawing substituents such as m-, or p-NO2. The
reason was not very clear. Meanwhile, amidoalkyl naphthols were also prepared just
for comparison under a relatively lower temperature of 120 °C (Table 5).
Lastly, we found that product 4a could be obtained from product 5a under
thermal conditions (Scheme 2) in the presence of [PyPS][HSO4]. Intermolecular
cyclo-condensation was accomplished when a molecular of NH3 was eliminated.
Therefore, we propose the following possible mechanism to account for the
reaction (Fig. 2). The reaction could be mechanistically considered to proceed
through the acylimine intermediate or ortho-quinone methides (O-QMs) interme-
diate. The subsequent addition of the b-naphthol to the acylimine or addition of the
urea to the O-QMs, followed by cyclization affords the corresponding products
naphthoxazinone 4.
Conclusions
In summary, the readily available pyridinium-based functionalized ionic liquid
[PSPy][HSO4] was prepared and it behaved as a novel, re-usable and efficient
catalyst for the preparation of a variety of amidoalkyl naphthol or naphthoxazinone
by one-pot three-component Ritter-type reaction under solvent-free thermal
123

Synthesis of 1,2-dihydro-1-arylnaphtho[1,2-e][1,3]oxazine-3-one catalyzed
2509
ArCHO
2
H
Ar
N
O
OH
Cat
+
O
solvent-free
O
1
H2N
NH2
4
3
Scheme 1 Synthesis of naphthoxazinone catalyzed by [PSPy][HSO4]
Table 4 [PyPS][HSO4] catalyzed three-component reaction for naphthoxazinone
Entry
Ar
Product
Time (min)
m.p. (°C) [Ref.]a
Isolated yields (%)
1
C6H5
4a
4b
4c
4d
4e
4f
60
60
216–218 [11]
200–202 [12]
189–191 [11]
167–169 [11]
181 dec. [11]
203–205 [11]
210–212 [11]
249–251 [12]
216–218 [11]
–
85
85
86
87
76
91
90
85
89
B5
B5
2
3-CH3OC6H4
4-CH3OC6H4
4-CH3C6H4
4-OHC6H4
4-FC6H4
3
60
4
60
5
60
6
60
7
4-ClC6H4
2-ClC6H4
4-BrC6H4
3-NO2C6H4
4-NO2C6H4
4g
4h
4i
60
8
60
9
60
10
11
4j
120
120
4k
–
Reaction conditions: naphthol (2.5 mmol), benzaldehyde (2.5 mmol), urea (3.5 mmol), [PyPS][HSO4]
(0.25 mmol), 150 °C
a
The products were identified by 1H NMR, and physical data (m.p.) with those reported in the
References
Table 5 [PyPS][HSO4] catalyzed three-component for amidoalkyl naphthols
Entry
Ar
Product
Time (min)
m.p. (°C)
Isolated yields (%)
1
2
C6H5
5a
5b
5c
5d
5e
5f
20
30
30
30
30
30
25
20
20
15
175–176
166–168
99–100
95
90
92
95
93
94
90
90
91
90
3-CH3OC6H4
4-CH3OC6H4
4-CH3C6H4
4-OHC6H4
4-ClC6H4
3
4
118–120
146–148
169–170
152–154
167–169
177–179
163–165
5
6
7
2-ClC6H4
5g
5h
5i
8
4-BrC6H4
3-NO2C6H4
4-NO2C6H4
9
10
5j
Reaction conditions: naphthol (2.5 mmol), benzaldehyde (2.5 mmol), urea (3.5 mmol), [PyPS][HSO4]
(0.25 mmol), 120 °C
123

2510
F. Dong et al.
H
N
O
HNCONH2
OH
Cat.
O
solvent-free
150 °C, 1h
4a
5a
Scheme 2 Convert 5a into 4a catalyzed by [PyPS][HSO4]
O
OH
Ar
N
NH2
N
SO3H
O
H
HSO4
Ar
Ar
N
O
Ar
HNCONH2
OH
H2N
NH2
O
O
H
4
5
OH
O
Ar
H2N
NH2
O
Fig. 2 Possible mechanism to account for the condensation reaction
conditions. This procedure offers several advantages including short reaction time,
good yields, operational simplicity, and being environmentally benign.
Experimental section
1
Melting points were determined on an X-6 data microscope melting apparatus. H
NMR spectra were recorded on a Bruker DRX300 (300 MHz) and 13C NMR spectra
on Bruker DRX300 (75.5 MHz) spectrometer. Mass spectra were obtained with an
automated Finnigan Trace Ultra-Trace DSQ LC–MS spectrometer. All chemicals
(AR grade) were commercially available and used directly without further
purification.
Synthesis of pyridinium-based functionalized ionic liquids (Py-FIL)
The pyridinium-based functionalized ionic liquids was prepared according to
1
reported methods [20] with some changes and the structure was analyzed by H
NMR and 13C NMR (Fig. 1).
123

Synthesis of 1,2-dihydro-1-arylnaphtho[1,2-e][1,3]oxazine-3-one catalyzed
2511
To a solution of 20.13 g (0.10 mol) of PPS in 10 mL of water was added 10.0 g
of sulfuric acid solution (98 %) (0.10 mol). The mixture was then stirred for 2 h at
80 °C. The combined solution was then dried under vacuum at 100 °C to remove
the water. The [PSPy][HSO4] produced was washed repeatedly with diethyl ether to
remove unreacted material and again dried under vacuum. Then, [PSPy][HSO4] was
obtained quantitatively as a colorless oil. The selected spectral data for pyridinium-
based functionalized halogen-free [PSPy][HSO4] are given below.
1HNMR (300 MHz, D2O): d 8.62 (d, J = 6.9 Hz, 2H, H-2, H-6), 8.30 (t,
J = 7.8 Hz, 1H, H-4), 7.84 (t, J = 6.9 Hz, 2H, H-3, H-5), 4.51 (t, J = 7.5 Hz, 2H,
N–CH2–C–C–SO3), 2.73 (t, J = 7.2 Hz, 2H, N–C–C–C–CH2–SO3), 2.18–2.23 (m,
2H, N–C–CH2–C–SO3). 13CNMR (75.5 MHz, D2O): d 146.35, 144.70, 128.82,
60.28, 47.48, 26.47.
General procedure for the synthesis of 1,2-dihydro-1-arylnaphtho
[1,2-e][1,3]oxazine (Product 4)
A
mixture of b-naphthol (2.5 mmol), aldehyde (2.5 mmol), and urea
(3.5 mmol), and [PSPy][HSO4] (0.25 mmol) was stirred at 150 °C for 60 min
(Scheme 2). On completion (monitored by TLC), the mixture was cooled to
50 °C, then ethanol (10 mL) was added to dilute the reaction mixture, which
was stirred continually for 5 min at 80 °C. The catalyst was separated by
filtration. The residue was kept at room temperature for a while and the solid
product was collected by filtration. The product 5 was found to be pure and no
further purification was necessary.
The selected data for naphthoxazinone:
1,2-Dihydro-1-(4-chlorophenyl)naphtho[1,2-e][1,3]oxazine-3-one (product 4 g
C18H12NO2Cl). White solid; m.p. 210–212 °C; 1H NMR (300 MHz, DMSO-d6): d,
8.91 (s, 1 H, NH), 8.01–7.31 (m, 10 H, Ar–H), 6.24 (s, 1 H, CH).
General procedure for the synthesis of amidoalkyl naphthols (Product 5)
A mixture of b-naphthol (2.5 mmol), aldehyde (2.5 mmol), and urea (2.5 mmol),
and [PSPy][HSO4] (0.25 mmol) was stirred at 120 °C for 15–30 min (Scheme 2).
On completion (monitored by TLC), water (2 mL) was added to the reaction
mixture, which was stirred continually for 5 min and then filtered. The solid crude
product was recrystallized from 95 % ethanol to afford pure product 4, which was
identified by 1H NMR and physical data (m.p.), and compared with those reported in
the literature.
1-((4-Chlorophenyl)(2-hydroxynaphthalen-1-yl)methyl)urea (product 5f, C18H15N2
O2Cl). White solid; m.p. 169–170 °C; 1H NMR (300 MHz, DMSO-d6): d 10.32 (s, 1H),
7.95–7.75 (m, 3H, Ar–H), 7.50–7.10 (m, 7H, Ar–H), 6.80 (s, 2H), 5.80 (s, 2H).
Acknowledgments We express our sincere thanks to the Ministry of Science and Technology of the
P.R. China (11C26213201395), Jiangsu Provincial Department of Education (JHB2011-52), and Key
Laboratory of Organic Synthesis of Jiangsu Province (KJS1112) for financial assistance.
123

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F. Dong et al.
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