Ultrasound-assisted one-pot synthesis of 1,3-oxazine derivatives catalysed by BF3-SiO2 under neat conditions

Article abstract of DOI:10.3184/174751912X13371662613770

An efficient and environment-friendly method for the synthesis of 1,3-oxazine derivatives has been developed using the ultrasound-mediated condensation of 2-naphthol with formaldehyde and primary amines under solvent-free condition at room temperature in

Full text of DOI:10.3184/174751912X13371662613770

398 RESEARCH PAPER
JULY, 398–401
JOURNAL OF CHEMICAL RESEARCH 2012
Ultrasound-assisted one-pot synthesis of 1,3-oxazine derivatives
catalysed by BF3–SiO2 under neat conditions
Mudumala Veeranarayana Reddy, Kwon Taek Lim, Jong Tae Kim and Yeon Tae Jeong*
Department of Image Science and Engineering, Pukyong National University, Busan, Korea 608-737
An efficient and environment-friendly method for the synthesis of 1,3-oxazine derivatives has been developed using
the ultrasound-mediated condensation of 2-naphthol with formaldehyde and primary amines under solvent-free
condition at room temperature in the presence of BF3-SiO2 to give the desired product in good to excellent yield.
This procedure provides several advantages over current methods including a simple work-up, cost effectiveness, a
reusable catalyst and shorter reaction times.
Keywords: 1,3-oxazines, BF3-SiO2, ultrasound irradiation, green synthesis
Non-polluting synthetic procedures are being developed,
because of increasing concerns of the harmful effects of
organic solvents on the environment. Ultrasound-promoted
reactions1 have attracted attention during the last few years to
accelerate a number of organic transformations.2
a facile one-pot synthesis of 1,3-oxazines by a three-compo-
nent coupling of 2-naphthol, formaldehyde and aromatic/
aliphatic/heterocyclic amines (3) in the presence of a catalytic
amount (10 mol %) of BF3–SiO2 under solvent-free ultrasound
irradiation at room temperature (Scheme 1).
Ultrasound induced organic transformations offer simple
experimental procedure, clean reaction, short reaction time,
high yields, and improved selectivity.3 Recently, a number
of heterocycles have been synthesised under solvent-free
conditions accelerated by ultrasound irradiation.4,5
The 1,3-oxazine ring system is a core structure present in a
number of biologically-active heterocycles possessing analge-
sic,6 anti-cancer,7 anti-HIV,8 and anti–ulcer activity.9 In addi-
tion, naphthoxine derivatives possess therapeutic potential
for the treatment of Parkinson’s disease.10 The syntheses of
dihydro-1,3-oxazines which have been previously reported by
several investigators involve a Mannich type condensation of a
Result and discussion
In order to investigate the ultrasonic effect on the three-compo-
nent coupling reaction in solvent-free condition at room tem-
perature in the presence of BF3–SiO2, we explored the reaction
of 2-naphthol, formaldehyde and aniline as a model.
We found that there was remarkable ultrasound and cata-
lytic effects on the one-pot in this coupling reaction. When the
three-component mixture in THF was kept at room tempera-
ture for 8h, none of the product was observed. (Table 1, entry
1), Only a low yield of product was obtained when this one-pot
reaction was carried out by refluxing for 3 h in the presence
of ZnCl2–SiO2 without sonication (Table 1, entry 2). Instead,
reasonable yield (60%) of product 4a was obtained when the
ZnCl2–SiO2-catalysed three-component reaction in THF was
carried out at room temperature for 2 h under ultrasound
irradiation (Table 1, entry 3). It seemed that the solvent-free
one-pot coupling took place sluggishly at room temperature in
20% yield even overnight without catalyst (Table 1, entry 4).
However, these methods involved a long reaction time and
gave an unacceptable yield. Therefore, our efforts were focused
on the search for a suitable catalyst. We examined; TiO2–SiO2,
PPA–SiO2 and BF3-SiO2 as catalysts for this reaction under
solvent-free condition at 80 °C. Long reaction times and low
transformation rates were in these experiments (Table 1, entries
5–7). Attempts were made to use ultrasound irradiation with
the same catalysts at room temperature, in solvent-free condi-
tions. The results are listed in Table 1. TiO2–SiO2 and PPA–
SiO2 were found to catalyse the reaction to give a moderate
yield over a long reaction time. Surprisingly, in the case of
BF3–SiO2 (Table 1, entry 10) the target product 4a was obtained
in 92% yields within 10 min at room temperature. Evidently,
the sonochemical effect might be the significant factor to the
high efficiency of the one-pot and solvent-free reactions.
phenol or naphthol with formaldehyde and a primary amine
11
using highly inflammable organic solvents
and alkaline
media.12 Further, research has led to mild, solvent free, water
and ionic liquid methods for the construction of these mole-
cules.13–15 However, many of these processes are associated
with several shortcomings such as long reaction times, high
reaction temperature, use of volatile and hazardous organic
solvents, and occurrence of side products. Hence, the develop-
ment of new and simple synthetic methods for the preparation
of heterocyclic compounds containing 1,3-oxazine derivatives
still remains an interesting challenge. Silica-supported boron
trifluoride, BF3–SiO2 is a bench-top catalyst which is easy
to handle, reusable, cheap, readily available, eco-friendly,
versatile and efficient for promotion of many acid-catalysed
organic reactions16–18 which we have examined for the synthe-
sis of 1,3-oxazine derivatives.
There are no reports on the synthesis of 1,3-oxazines under
ultrasound irradiation in solvent-free at room temperature
mediated by BF3–SiO2. Our main target was to develop a green
organic reaction methodology which was faster and cleaner
than conventional reactions as part of our ongoing research
program on the development of clean protocols,19,20 We report
Scheme 1 Synthesis of 1,3-oxazine derivatives.
* Correspondent. E-mail: ytjeong@pknu.ac.kr

JOURNAL OF CHEMICAL RESEARCH 2012 399
Table 1 Coupling of 2-naphthol (1 mmol), formaldehyde (2.2 mmol) and aniline (1 mmol) under different conditions
Entry
Solvent
Catalyst/mol %
Conditions
Time/min
Yield/%a
1
2
THF
-
r.t
480
180
120
Overnight
150
190
60
0
25
THF
ZnCl2–SiO2(10)
ZnCl2–SiO2(10)
-
Reflux
US/r.t
rt
3
THF
60
4
Solvent-free
Solvent-free
Solvent-free
Solvent-free
Solvent-free
Solvent-free
Solvent-free
Solvent-free
Solvent-free
Solvent-free
20
5
TiO2–SiO2(10)
PPA–SiO2(10)
BF3–SiO2(10)
TiO2–SiO2(10)
PPA–SiO2(10)
BF3–SiO2 (10)
BF3–SiO2 (2)
BF3–SiO2 (5)
BF3–SiO2 (15)
80 °C
80 °C
80 °C
US/r.t
US/r.t
US/r.t
US/r.t
US/r.t
US/r.t
40
6
55
7
80
8
80
65
9
65
72
10b
11
12
13
10
92, 91. 90
35
10
10
65
92
10
a Isolated yield.
b Catalyst was reused three times.
US, ultrasound.
Subsequently, catalyst loading was optimised and 10 mol%
BF3–SiO2 provided the maximum yield in minimum time
(Table 1, entry 10). A further increase in the amount of BF3–
SiO2 did not have any significant effect on the product yield
or reaction time, whereas the yield was reduced by decreasing
the amount of BF3–SiO2 (Table 1, entries 11–13). The catalytic
activity of the recycled BF3–SiO2 was also examined. BF3–
SiO2 could be re-used three times in the reaction without
noticeable loss of activity (Table 1, entry 10).
Based on the optimised reaction conditions, a group of 1,3-
oxazine derivatives were synthesised by this reaction using dif-
ferent aromatic/aliphatic/heterocyclic amines. In all the cases,
the reaction proceeded smoothly at room temperature and gave
good to excellent yields. To find the specific effect of ultra-
sound on this reaction, all the previously mentioned reactions
were carried out under the same conditions in the absence of
ultrasound irradiation (Table 2). It was observed that the reac-
tion times increased considerably and the yields of the prod-
ucts decreased under conventional reflux conditions. Thus,
ultrasonic irradiation was found to have a beneficial effect on
the synthesis of 1,3-oxazine derivatives over conventional
heating and offered significant improvements in terms of sim-
plicity and green aspects by avoiding a high temperature. In
comparison with conventional methods, the main advantages
of our procedure are the significant decrease of reaction time
and improvement of yields. While conventional methods
required 1 h at reflux, when ultrasonic irradiation is employed,
the products were obtained in 10 min with better yields.
Another advantage of the present method is the absence of an
additional purification step.
Scheme 2 Tentative mechanism for the formation of 1,3-oxazines (4a).

400 JOURNAL OF CHEMICAL RESEARCH 2012
Table 2 Synthesis of 1,3-oxazine derivatives (4a–r) under ultrasonic irradiation.a
Entry
R
Product
Sonochemical method
Traditional method
M.p. /°C
Time/min
Yieldb/%
Time/min
Yieldb/%
Found
Reported
(49–51)14
1
2
C6H5
4-BrC6H4
4a
4b
4c
4d
4e
4f
4g
4h
4i
10
13
15
14
10
11
18
20
14
18
17
20
92
90
89
89
94
94
90
85
89
88
85
85
60
70
80
78
70
75
81
80
85
70
78
72
65
60
48–50
116–117
108–110
57–58
77–78
89–90
164–166
Liquid
55–57
110–112
103–105
98–100
(115–117)14
(109.5)13
(56.9)13
3
4-ClC6H4
60
4
4-FC6H4
68
5
4-OMeC6H4
4-MeC6H4
4-NO2C6H4
2,4-Cl2C6H3
2-MeC6H4
2-NO2C6H4
4-Cl,2-OHC6H3
2,6(CH-
62
(78–80)14
(88–90)14
(165–167)14
(Liquid)13
(56–58)14
(110–112)14
–
6
65
7
100
120
80
8
9
10
11
12
4j
4k
4l
95
115
125
–
(CH3)2)2C6H3
2-OHC6H4
13
14
4m
4n
14
14
86
92
100
75
72
73
98–100
–
–
255–257
15
4o
14
91
65
79
164–166
–
16
17
C6H5CH2
C4H9
4p
4q
16
28
90
80
89
140
72
56
54–56
136–138
(55–56)12
(138–140)13
18
4r
19
85
120
62
43–45
(43–44)12
a Reaction of 2-naphthol (1 mmol), formaldehyde (2.2 mmol) and amines (1 mmol) catalysed by BF3-SiO2(10%) under ultrasonic
waves in solvent-free condition at room temperature.
b Isolated yield.
The reaction of aromatic/aliphatic/heterocyclic amines with
formaldehyde and 2-naphthol in the presence of 10 mol %
BF3–SiO2 under ultrasound irradiation at room temperature
in solvent- free conditions resulted in the formation of the
1,3-oxazine derivatives (4a–r) in good to excellent yields
(Table 2). It was found that there was no noticeable electron
and position effects on the aromatic/heterocyclic amines
containing o-,m- and p-electron withdrawing and donating
substituents in these three-component couplings. Apart from
the aromatic/heterocyclic amines, some aliphatic amines
were also selected to carry out the three-component couplings.
Benzylamine (Table 2, entry 16), gave the target product 4p in
reasonable yield, but only moderate yield of products were
obtained from cyclohexylamine and n-butylamine (Table 2,
entries 17 and 18). These results reveal that aliphatic amines
were not as effective as those aromatic/heterocyclic amines for
the preparation of 1,3-oxazine derivatives (4a–r).
The plausible mechanism is depicted in Scheme 2. Initially,
BF3–SiO2 serves as a Lewis acid catalyst for the reaction of
aniline and formaldehyde to give the imine (I). Similarly,
the diene (II) was formed through de-aromatisation of the
naphthol ring by reaction with formaldehyde. The diene (II)
and imine (I) then undergo an aromatisation reaction in the
presence of BF3–SiO2 to afford corresponding 1,3-oxazine
(4a). The structures of all the synthesised compounds were
established by their 1H and 13CNMR and ESI-MS analyses and
these results are in good agreement with the reported data.
In conclusion, we have found an efficient and practical
procedure for the preparation of 1,3-oxazine derivatives (4a–r)
from 2-naphthol with formaldehyde and aromatic/aliphatic/
heterocyclic amines in the presence of 10 mol% BF3–SiO2
under ultrasound irradiation at room temperature using
solvent- free conditions. Based on those results, we have shown
that compared to traditional methods (reflux method), ultra-
sound irradiation can speed up the reaction and is more conve-
nient and efficient. Reusability, eco-friendly, inexpensive short
reaction times, high yields and easy workup are advantages of
this protocol.
Experimental
Chemicals were purchased from Aldrich and Alfaaesar Chemical
Companies. NMR spectra were recorded in ppm in CDCl3 on a Jeol
JNM ECP 400 NMR instrument using TMS as internal standard.
An Elmasonic S 100 H (with a frequency of 35 kHz and a nominal
power 550 W) ultrasonic bath was used for ultrasonic irradiation. It
had built-in heating, and was thermostatically adjustable 30–80 °C.
The reaction vessel was placed inside the ultrasonic bath containing
water. Mass spectra were recorded by the Jeol JMS-700 mass
spectrometer, respectively. All melting points were determined using
open capillaries on an Electrothermal-9100 (Japan) instrument.
Synthesis of 1,3-oxazine derivatives; general procedure
A mixture of 2-naphthol (1 mmol), 37% aqueous formaldehyde
(2.2 mmol) and the aromatic/aliphatic/heterocyclic amine (1 mmol) in
the presence of BF3–SiO2 (10 mol%) were placed on a 25 mL beaker
and exposed to ultrasonic irradiation at room temperature for appro-
priate time (Table 2) in solvent-free condition. The progress of the
reaction was monitored by TLC. After completion of the reaction,
the mixture was washed with chloroform and filtered to recover the
catalyst. The filtrate was evaporated, and the crude product was
recrystallised from ethanol to afford pure 1,3-oxazine derivatives in
good to excellent yields.
4-Chloro-2-(1H-naphtho[1,2-e][1,3]oxazin-2(3H)-yl)phenol (4k):
Yield; 85%; pale yellow solid; m.p. 103–105 °C. 1H NMR (400 MHz,
CDCl3): δ 4.68 (s, 2H), 5.08 (s, 2H), 6.51 (s, 1H), 6.92 (d, J = 8.5 Hz,
1H), 7.06 (dd, J = 2.3, 10.9 Hz, 1H), 7.15 (dd, J = 2.0, 10.9 Hz, 2H)
7.40 (t, J = 7.2 Hz, 1H), 7.49 (dd, J = 5.4, 14.2 Hz, 1H), 7.56 (d,
J = 8.2 Hz, 1H), 7.73 (d, J = 9.2 Hz, 1H), 7.82 (d, J = 8.2 Hz, 1H). 13
C
NMR (100 MHz, CDCl3): δ 49.7, 81.6, 112.4, 116.0, 119.7, 120.9,
124.2, 124.8, 125.4, 126.5, 127.9, 128.9, 129.5, 132.8, 137.4, 151.1.
HRMS (ESI, m/z): Calcd for C18H14ClNO2 (M+H+) 311.0713; found:
311. 0710.
2,3-Dihydro-2-(2,6-diisopropylphenyl)-1H-naphtho[1,2-e][1,3]-
1
oxazine (4l): Yield; 85%; white solid; m.p. 98–100 °C. H NMR
(400 MHz, CDCl3): δ 1.20 (t, J = 6.8 Hz, 12H), 3.27–341 (m, 2H),
4.65 (s, 2H), 5.12 (s, 2H), 7.16 (t, J = 7.1 Hz, 3H), 7.27 (d, J = 8.2Hz,

JOURNAL OF CHEMICAL RESEARCH 2012 401
1H), 7.35 (t, J = 7.1 Hz, 1H), 7.42–7.46 (q, 1H), 7.56 (d, J = 8.5 Hz,
1H), 7.67 (d, J = 8.8 Hz, 1H), 7.78 (d, J = 7.8 Hz, 1H). 13C NMR
(100 MHz, CDCl3): δ 25.3, 26.1, 29.8, 50.1, 82.2, 115.0, 120.6, 122.1,
124.7, 125.2, 127.7, 128.7, 129.1, 129.7, 130.0, 132.4, 144.0, 150.6,
153.7. HRMS (ESI, m/z): Calcd for C24H27NO (M+H+) 345.2093;
found: 345.2095.
Received 6 April 2012; accepted 16 April 2012
Paper 1201217 doi: 10.3184/174751912X13371662613770
Published online: 26 June 2012
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This research work was supported by the second stage of BK21
Program.

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