K2CO3/H2O in [omim][BF4] ionic liquid: A green medium for efficient room-temperature synthesis of N-substituted 1,4-benzoxazin-3-ones

Article abstract of DOI:10.1002/jhet.866

A medium consisting of K₂CO₃ and H₂O in [omim][BF₄] ionic liquid (IL) was used to synthesize N-substituted 2H-benzo[b][1,4]oxazin-3(4H)-one derivatives from their corresponding o-aminophenols and 2-bromoalkanoates. As a result, chemoselective formation of benzoxazinones in high yields has been observed at room temperature. After the reactions and separation of the products, the IL was recovered and successfully reused in subsequent reactions without significant loss of activity.

Full text of DOI:10.1002/jhet.866

July 2012
K2CO3/H2O in [omim][BF4] Ionic Liquid: A Green Medium
for Efficient Room-Temperature Synthesis of
N-Substituted 1,4-Benzoxazin-3-ones
933
*
*
Ali Sharifi, Mehdi Barazandeh, M. Saeed Abaee, and Mojtaba Mirzaei
Organic Chemistry Department, Chemistry & Chemical Engineering Research Center of Iran,
Tehran, Iran
*
E-mail: sharifi@ccerci.ac.ir or abaee@ccerci.ac.ir
Received October 17, 2010
DOI 10.1002/jhet.866
View this article online at wileyonlinelibrary.com.
A medium consisting of K2CO3 and H2O in [omim][BF4] ionic liquid (IL) was used to synthesize
N-substituted 2H-benzo[b][1,4]oxazin-3(4H)-one derivatives from their corresponding o-aminophenols
and 2-bromoalkanoates. As a result, chemoselective formation of benzoxazinones in high yields has been
observed at room temperature. After the reactions and separation of the products, the IL was recovered and
successfully reused in subsequent reactions without significant loss of activity.
J. Heterocyclic Chem., 49, 933 (2012).
INTRODUCTION
reaction is involved, an external stimulant such as micro-
wave irradiation is used, or limited range of substrates is
used.
In line with recent environmental mandates to minimize
the use of toxic organic solvents or replace them with safer
alternatives, ionic liquids (ILs) have emerged as a new
class of stable, nonvolatile, and inert media for various
organic transformations [1]. More importantly, in many
instances, their use has been accompanied with dramatic
rate and selectivity enhancements [2]. In this regard, a
particular application has been the use of potassium
carbonate (K2CO3) to boost the synthetic transformations
that require the removal of acidic hydrogens in their initial
steps [3].
Extensive investigations have been carried out in recent
years on 2H-benzo[b][1,4]oxazin-3(4H)-one scaffold (e.g.,
compound 3). These types of structures are very important
in synthetic [4] and medicinal organic chemistry [5] and
contribute to the structure of many biologically active
synthetic and natural products [6]. In the majority of the
available methods, condensation of o-aminophenols or
o-nitrophenols with a-substituted carbonyl derivatives or
their synthetic equivalents has been used as the main path-
way for the synthesis of 3 [7]. However, o-aminophenols
have usually been the preferred starting materials as in their
ring closure, the extra steps of O-alkylation and nitro group
reduction associated with the use of o-nitrophenols are
skipped [8]. Nevertheless, in the majority of the available
methods for the synthesis of 1,4-benzoxazin-3-ones either
high-temperature treatment is required, more than one-step
In the framework of our studies on heterocyclic systems
[9], and in continuation of our previous investigations on
the development of environmentally friendly procedures
[10], we recently communicated our preliminary results
on IL-mediated synthesis of 3 using 1,8-diazabicyclo
[5.4.0]undec-7-ene (DBU) where mainly unsubstituted
o-aminophenols underwent room-temperature annulation
with 2-bromoalkanoates [11]. In continuation, we now
wish to report the extension of the methodology in
cyclization of N-substituted substrates (Scheme 1) that
are known to annulate under relatively harsh conditions
[7(a)]. In the current work, reactions occurred at room
temperature using K2CO3 and water, the conditions were
noticeably mild, and the IL medium was efficiently
recycled into the subsequent reactions.
RESULTS AND DISCUSSIONS
First, we obtained the optimized conditions using the
reaction of 2-(benzylamino)phenol (1a) with ethyl 2-bro-
mopropionate (2b) as shown in Table 1. KF, NaOEt, and
Et3N in [omim][BF4] were used as the IL induced no signif-
icant reaction (entries 1–3). Among carbonate bases (entries
4–6), only K2CO3 caused slight conversion of the reactants
to product 3ab (entry 6). Addition of a few drops of water
© 2012 HeteroCorporation

934
A. Sharifi, M. Barazandeh, M. S. Abaee, and M. Mirzaei
Vol 49
Scheme 1
to the mixtures improved the yield of all reactions (entries
7–11). Consequently, in the presence of the IL and water,
again K2CO3 showed the best performance leading to nearly
quantitative formation of 3ab in much shorter time period
(entry 12). In the absence of the IL, the yield dropped
dramatically illustrating the crucial role of [omim][BF4] in
the progress of the reaction (entry 13). Alteration of the
cationic or anionic components of the IL also led to lower
yields of the product (entries 14–20).
The optimized conditions ([omim][BF4]/K2CO3/H2O)
were then used to evaluate the generality of the method
(Table 2). Reactions of 1a–c with 2a rapidly gave single
products 3aa, 3ba, and 3ca, respectively (entries 1–3).
Similarly, reactions with secondary 2-bromoalkanoate
(2c) led to high-yield formation of products 3ac, 3bc,
and 3cc (entries 4–6). Interestingly, reactions of 2d, a
bromoalkanoate with tertiary carbon at its a position,
proceeded efficiently (entries 7–9) giving the respective
products but in longer times. Because of high-steric bulks,
synthesis of these compounds is not very facile, with few
low-yielding procedures for their synthesis available in
the literature [12].
was obtained, respectively, illustrating the efficiency of
the recovered IL.
A mechanism is proposed for the process based on
the observed results, as shown in Scheme 2. Initially,
K2CO3 could deprotonate the hydroxy group of the
o-aminophenol to produce the corresponding phenolate
to attack compound 2. The intramolecular annulation of
the ethyl aminophenoxyalkanoate intermediate would then
give the product. This was supported by low-temperature
separation of the more sluggish intermediate 3a0d for the
reaction of 1a with 2d.
In summary, the versatility and efficiency of the current
method could be easily concluded by the comparison of the
results with previous related investigations [13]. The
present work shows the first general methodology for the
facile room-temperature annulation of N-substituted o-
aminophenols with various types of 2-bromoalkanoates.
Table 1
Optimization of the reaction conditions.
Entry
Conditions
Time (h)
Yield (%)a
To further illustrate the generality of the procedure, var-
ious N-furanylmethyl-substituted o-aminophenols were
also subjected to the optimized annulation conditions. As
summarized in Table 3, 2-((furan-2-ylmethyl)amino)
phenol (1d) reacted efficiently with 2a (entry 1), 2b (entry
2), and 2d (entry 3) to produce the expected products in
high yields. Similar results were also observed for the
reactions of electron-releasing (entries 4 and 5) and
electron-withdrawing-substituted substrates (entries 6 and
7), 1e and 1f, respectively.
In the majority of the examples, single products formed
rapidly at room temperature and easily separated from the
reaction mixtures by a simple ethereal extraction allowing
efficient recovery of the IL and its reuse in subsequent
reactions without significant loss of activity. This was
shown by conducting five reactions of 1a with 2b in a
row, while each time the recovered IL was reused in the
next reaction. As a result, 95, 94, 92, 89, and 89% of 3ab
1
2
3
4
5
6
7
8
[omim][BF4]/KF
[omim][BF4]/NaOEt
[omim][BF4]/NEt3
24
24
24
24
24
24
24
24
24
24
24
2
24
2
2
2
2
0
<5
<5
0
0
10
5
[omim][BF4]/Na2CO3
[omim][BF4]/NaHCO3
[omim][BF4]/K2CO3
[omim][BF4]/KF/H2O
[omim][BF4]/NaOEt/H2O
[omim][BF4]/NEt3/H2O
[omim][BF4]/Na2CO3/H2O
[omim][BF4]/NaHCO3/H2O
[omim][BF4]/K2CO3/H2O
K2CO3/H2O
[bmim][BF4]/K2CO3/H2O
[omim]Cl/K2CO3/H2O
[omim][NO3]/K2CO3/H2O
[opy][BF4]/K2CO3/H2O
[bpy][BF4]/K2CO3/H2O
[omim][PF6]/K2CO3/H2O
[bmim][PF6]/K2CO3/H2O
5
9
<5
15
5
10
11
12
13
14
15
16
17
18
19
20
95
<5
91
50
26
81
68
18
9
2
2
2
aIsolated yields.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

July 2012
K2CO3/H2O in [omim][BF4] Ionic Liquid: A Green Medium for Efficient
Room-Temperature Synthesis of N-Substituted 1,4-Benzoxazin-3-ones
935
Table 2
IL-mediated synthesis of N-substituted benzoxazinones.
Entry
o-Aminophenols
2-Bromoalkanoate
Product
Time (h)
Yield (%)a
1
2
3
4
5
6
7
8
9
1a
1b
1c
1a
1b
1c
1a
1b
1c
2a
2a
2a
2c
2c
2c
2d
2d
2d
3aa
3ba
3ca
3ac
3bc
3cc
3ad
3bd
3cd
2
2
4
3
4
82
86
78
98
95
94
88
86
85
8
24
24
48
aIsolated yields.
Ultra Shield™ (500 MHz) as CDCl3 solutions using TMS as an
internal standard reference. Elemental analyses were performed
using a Thermo Finnigan Flash EA 1112 instrument. Mass spectra
were obtained on a Fisons Trio 1000 instrument at ionization
potential of 70 eV. Thin-layer chromatography (TLC) experiments
were carried out on precoated silicagel plates using EtOAc/hexane
(1:4) as the eluent. Solvents and reagents were purchased
from commercial sources. ILs, 1-octyl-3-methylimidazolium
tetrafluoroborate ([omim][BF4]), 1-buyl-3-methylimidazolium
High yields of the products, chemoselectivity of the
reaction, efficient recovery of the IL, and successful
engagement of tertiary 2-bromoalkanoates in the reaction
are the main advantages of the methodology. Application
of the procedure in annulation of o-aminothiophenols and
phenylenediamines with various a-substituted carbonyl
compounds is currently under study and will be reported
in due course.
tetrafluoroborate
([bmim][BF4]),
N-octylpyridinium
tetra-
fluoroborate ([opy][BF4]), N-butylpyridinium tetrafluoroborate
([bpy][BF4]), 1-octyl-3-methylimidazolium chloride ([omim]Cl),
1-octyl-3-methylimidazolium hexafluorophosphate ([omim][PF6]),
1-buyl-3-methylimidazolium hexafluorophosphate ([bmim][PF6]),
and 1-octyl-3-methylimidazolium nitrate ([omim][NO3]), were
prepared using known procedures [14]. Products 3aa [11], 3ab
EXPERIMENTAL
General.
Melting points are uncorrected. IR spectra were
recorded using KBr disks on a Shimadzu IRPrestige-21 infrared
spectrometer. NMR spectra were obtained on a FT-NMR Bruker
Table 3
IL-mediated synthesis of N-furanylmethyl benzoxazinones.
Entry
o-Aminophenols
2-Bromoalkanoate
Product
Time (h)
Yield (%)a
1
2
3
4
5
6
7
1d
1d
1d
1e
1e
1f
2a
2b
2d
2a
2b
2a
2b
3da
3db
3dd
3ea
3eb
3fa
1.5
1.5
24
1
1
6
96
85
92
98
80
95
85
1f
3fb
6
aIsolated yields.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

936
A. Sharifi, M. Barazandeh, M. S. Abaee, and M. Mirzaei
Vol 49
Scheme 2. The proposed mechanism.
4-(4-Methoxybenzyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (3ba).
White solid; mp 88–91ꢁC; IR (KBr) 3064, 2951, 2897, 1687, 1608,
1
1498, 1402, 1251 cm-1; H NMR (500 MHz, CDCl3) d: 7.20 (d,
J = 8, 2H), 7.00–6.92 (m, 4H), 6.85 (d, J = 8, 2H), 5.10 (s, 2H),
4.71 (s, 2H), 3.77 (s, 3H); 13C NMR (125 MHz, CDCl3) d: 164.9,
159.2, 145.5, 129.0, 128.3, 128.2, 124.1, 122.9, 117.1, 115.9,
114.5, 67.9, 55.5, 44.6; MS 269, 121; Anal. Calcd for C16H15NO3:
C, 71.36; H, 5.61; N, 5.20. Found: C, 71.42; H, 5.61; N, 4.91%.
4-(4-Chlorobenzyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (3ca).
Light yellow solid; mp 82–84ꢁC; IR (KBr) 3043, 2927, 2848,
1681, 1595, 1494, 1396, 1049 cm-1; 1H NMR (500 MHz,
CDCl3) d: 7.29 (d, J = 8.5 Hz, 2H), 7.19 (d, J = 8.5 Hz, 2H),
7.01–6.96 (m, 2H), 6.91 (ddd, J = 1.5, 7, 8 Hz, 1H), 6.84 (d,
J = 7.9 Hz, 1H), 5.12 (s, 2H), 4.71 (s, 2H); 13C NMR (125
MHz, CDCl3) d: 165.2, 145.9, 135.0, 133.9, 129.6, 129.0,
128.6, 124.7, 123.3, 117.6, 116.0, 68.2, 44.9; MS 273, 127, 125;
Anal. Calcd for C15H12ClNO2: C, 65.82; H, 4.42; N, 5.12.
Found: C, 65.80; H, 4.55; N, 5.01%.
4-Benzyl-2-ethyl-2H-benzo[b][1,4]oxazin-3(4H)-one (3ac).
Light yellow solid; mp 52–54ꢁC; IR (KBr) 3034, 2968, 1672,
1597, 1498, 1458, 1398 cm-1; H NMR (500 MHz, CDCl3) d:
1
[11], 3ad [11], 3da [7(a)], 3ea [7(a)], 3eb [7(a)], 3fa [7(a)], and 3fb
[7(a)] were known and their identity was confirmed by comparison
of their spectroscopic data with the available literature. All other
products were new and were characterized based on their 1H NMR,
13C NMR, IR, and mass spectra and elemental analyses.
7.34–7.31 (m, 2H), 7.27–7.24 (m, 3H), 7.02 (dd, J = 8, 1.5
Hz, 1H), 6.98 (ddd, J = 1.5, 6.5, 7 Hz, 1H), 6.90 (ddd, J =
1.5, 7, 8 Hz, 1H), 6.87 (dd, J = 1.5, 8 Hz, 1H), 5.24 (d, J = 16
Hz, 1H), 5.07 (d, J = 16 Hz, 1H), 4.63 (dd, J = 8.5, 5 Hz,
1H), 2.03–1.94 (m, 2H), 1.15 (t, J = 7.4 Hz, 3H); 13C NMR
(125 MHz, CDCl3) d: 167.0, 144.4, 136.6, 129.3, 129.2,
127.7, 126.8, 124.3, 122.8, 117.7, 115.5, 78.7, 45.4, 24.2, 9.8;
MS 267, 196, 120, 91; Anal. Calcd for C17H17NO2: C, 76.38;
H, 6.41; N, 5.24. Found: C, 76.01; H, 6.41; N, 4.98%.
Typical experimental procedure.
A mixture of 1a (200
mg, 1 mmol), water (0.1 mL), and K2CO3 (166 mg, 1.2 mmol)
was added to [omim][BF4] (0.78 mL, 3 mmol). After 5 min
stirring, 2b (217 mg, 1.2 mmol) was added to the mixture and
stirring continued at room temperature. The progress of the
reaction was monitored by TLC. After 2 h, the reaction mixture
was extracted with diethyl ether (3 ꢀ 10 mL). The organic
phase was washed with brine (20 mL), dried over anhydrous
Na2SO4, and concentrated under reduced pressure. The product
was obtained by column chromatography of the solid residue
using silica gel and EtOAc/hexanes (1:4) as the eluent. The IL
was dissolved in CH2Cl2 and filtered to remove any residual of
K2CO3. The volatile content of the IL was removed using a
rotary evaporator. Product 3ab was obtained in 95% (242 mg)
yield.
2-Ethyl-4-(4-methoxybenzyl)-2H-benzo[b][1,4]oxazin-3 (4H)-
one (3bc).
White solid; mp 61–63ꢁC; IR (KBr) 3026, 2968,
2929, 2845, 1674, 1598, 1502, 1396, 1309 cm-1; H NMR (500
MHz, CDCl3) d: 7.18 (d, J = 8.5 Hz, 2H), 6.98 (d, J = 7 Hz,
1H), 6.97–6.93 (m, 1H), 6.89–6.87 (m, 2H), 6.84 (d, J = 8.5 Hz,
2H), 5.16 (d, J = 16 Hz, 1H), 5.00 (d, J = 16 Hz, 1H), 4.58 (dd,
J = 4.5, 8.5 Hz, 1H), 3.77 (s, 3H), 2.02–1.89 (m, 2H), 1.12 (t, J
= 7.5 Hz, 3H); 13C NMR (125 MHz, CDCl3) d: 169.0, 161.3,
146.5, 131.3, 130.7, 130.3, 126.3, 124.8, 119.8, 117.8, 116.7,
80.8, 57.7, 47.0, 26.3, 12.0; MS 297, 121; Anal. Calcd for
C18H19NO3: C, 72.71; H, 6.44; N, 4.71. Found: C, 72.69; H,
6.44; N, 4.43%.
1
Spectral data.
one (3aa).
4-Benzyl-2H-benzo[b][1,4]oxazin-3(4H)-
White solid; mp 66–68ꢁC; IR (KBr) 1680, 1595,
4-(4-Chlorobenzyl)-2-ethyl-2H-benzo[b][1,4]oxazin-3(4H)-one
1498, 1394, 1321 cm-1; 1H NMR (500 MHz, CDCl3) d: 7.34–7.31
(m, 2H), 7.27–7.23 (m, 3H), 7.01–6.95 (m, 2H), 6.92–6.88
(m, 2H), 5.17 (s, 2H), 4.73 (s, 2H); 13C NMR (125 MHz, CDCl3)
d: 165.2, 145.8, 136.5, 129.4, 129.3, 128.0, 127.1, 124.5, 123.3,
117.5, 116.2, 68.2, 45.5; MS 239, 148, 120, 91; Anal. Calcd for
C15H13NO2: C, 75.30; H, 5.48; N, 5.85. Found: C, 76.36; H, 5.58;
N, 5.32%.
(3cc). Light yellow solid; mp 67–69ꢁC; IR (KBr) 3057, 2970,
1
2927, 2864, 1685, 1595, 1496, 1450, 1396 cm-1; H NMR (500
MHz, CDCl3) d: 7.28 (d, J = 8.5 Hz, 2H), 7.17 (d, J = 8.5 Hz,
2H), 7.02 (dd, J = 1.5, 8 Hz, 1H), 6.98 (ddd, J = 1.5, 7.5, 7.5
Hz, 1H), 6.91 (ddd, J = 1.5, 7.5, 8 Hz, 1H), 6.81 (dd, J = 1.5,
7 Hz, 1H), 5.17 (dd, J = 16 Hz, 1H), 5.04 (dd, J = 16 Hz, 1H),
4.60 (dd, J = 4.5, 8.5 Hz, 1H), 2.03–1.89 (m, 2H), 1.13 (t, J =
7.5 Hz, 3H); 13C NMR (125 MHz, CDCl3) d: 167.1, 144.6,
135.2, 133.7, 129.5, 129.1, 128.4, 124.5, 122.9, 117.9, 115.5,
78.7, 44.9, 24.2, 9.9; MS 301, 127, 125; Anal. Calcd for
C17H16ClNO2: C, 67.66; H, 5.34; N, 4.64. Found: C, 67.47; H,
5.31; N, 4.10%.
4-Benzyl-2-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one (3ab).
Light yellow solid; mp 53–55ꢁC; IR (KBr) 3030, 2933, 1689,
1604, 1500, 1394, 1251 cm-1; 1H NMR (500 MHz, CDCl3)
d: 7.34–7.31 (m, 2H), 7.27–7.24 (m, 3H), 7.01 (dd, J = 2,
7.5 Hz, 1H), 6.97 (ddd, J = 2, 7, 7.5 Hz, 1H), 6.92 (ddd, J = 2,
7, 7.5 Hz, 1H), 6.89 (dd, J = 2, 7 Hz, 1H), 5.18 (d, J = 16 Hz,
1H), 5.12 (d, J = 16 Hz, 1H), 4.78 (q, J = 6.8 Hz, 1H), 1.65
(d, J = 6.8 Hz, 3H); 13C NMR (125 MHz, CDCl3) d: 167.3,
144.7, 136.5, 129.3, 129.1, 127.6, 126.7, 124.2, 122.8, 117.5,
115.7, 73.8, 45.5, 16.7; MS 253, 196, 120, 91; Anal. Calcd for
C16H15NO2: C, 75.87; H, 5.97; N, 5.53. Found: C, 75.89;
H, 5.98; N, 5.18%.
4-Benzyl-2,2-dimethyl-2H-benzo[b][1,4]oxazin-3(4H)-one (3ad).
Light yellow solid; mp 67–69ꢁC; IR (KBr) 3034, 2972, 2933, 1680,
1
1598, 1496, 1456, 1390, 1253 cm-1; H NMR (500 MHz, CDCl3)
d: 7.34–7.31 (m, 2H), 7.26–7.23 (m, 3H), 6.98–6.96 (m, 2H), 6.89
(ddd, J = 2, 7, 7.5 Hz, 1H), 6.84 (d, J = 7.5 Hz, 1H), 5.14 (s, 2H),
1.60 (s, 6H); 13C NMR (125 MHz, CDCl3) d: 169.3, 143.7, 136.7,
129.4, 129.1, 127.6, 126.6, 124.1, 122.5, 117.9, 115.3, 78.1, 45.7,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

July 2012
K2CO3/H2O in [omim][BF4] Ionic Liquid: A Green Medium for Efficient
Room-Temperature Synthesis of N-Substituted 1,4-Benzoxazin-3-ones
937
24.1; MS 267, 196, 134, 91; Anal. Calcd for C17H17NO2: C, 76.38;
H, 6.41; N, 5.24. Found: C, 76.03; H, 6.42; N, 4.85%.
Press: Oxford, 2002; (b) Hardacre, C.; Holbrey, J.; Nieuwenhuyzen, M.;
Youngs, T. G. A. Acc Chem Res 2007, 40, 1146.
[3] (a) Kmentová, I.; Gotov, B.; Solcániová, E.; Toma, S. Green
Chem 2002, 4, 103; (b) Hu, Y.; Chen, Z.; Le, L.; Zheng, Q. Synth
Commun 2004, 34, 2039.
4-(4-Methoxybenzyl)-2,2-dimethyl-2H-benzo[b][1,4]oxazin-3
(4H)-one (3bd).
Light yellow solid; mp 65–67ꢁC; IR (KBr)
3066, 2972, 2931, 2837, 1672, 1610, 1506, 1392, 1253, 1026
ꢀ
ꢀ
[4] (a) Ilas, J.; Štefanic Anderluh, P.; Sollner Dolenc, M.; Kikelj,
D. Tetrahedron 2005, 61, 7325; (b) Zuo, H.; Meng, L.; Ghate, M.; Hwang,
K. H.; Cho, Y. K.; Chandrasekhar, S.; Reddy, Ch. R.; Shin, D. S.
Tetrahedron Lett 2008, 49, 3827; (c) Shridhar, D. R.; Gandhi, S. S.;
Srinivasa Rao, K. Synthesis 1982, 986.
1
cm-1; H NMR (500 MHz, CDCl3) d: 7.17 (d, J = 8.5 Hz, 2H),
6.96–6.94 (m, 2H), 6.90–6.87 (m, 2H), 6.84 (d, J = 8.5 Hz,
2H), 5.07 (s, 2H), 3.77 (s, 3H), 1.58 (s, 6H); 13C NMR (125
MHz, CDCl3) d: 169.5, 159.4, 143.9, 129.7, 129.0, 128.3,
124.3, 122.7, 118.1, 115.5, 114.8, 78.3, 55.7, 45.4, 24.4; MS
297, 134, 121; Anal. Calcd for C18H19NO3: C, 72.71; H, 6.44;
N, 4.71. Found: C, 72.57; H, 6.44; N, 4.48%.
4-(4-Chlorobenzyl)-2,2-dimethyl-2H-benzo[b][1,4]oxazin-3
(4H)-one (3cd). Light yellow solid; mp 97–99ꢁC; IR (KBr)
3061, 2976, 2929, 2864, 1668, 1600, 1496, 1392, 1255 cm-1;
1H NMR (500 MHz, CDCl3) d: 7.29 (d, J = 8.5 Hz, 2H), 7.16
(d, J = 8.5 Hz, 2H), 6.97 (d, J = 4.1 Hz, 2H), 6.90–6.87 (m,
1H), 6.78 (d, J = 8 Hz, 1H), 5.09 (s, 2H), 1.57 (s, 6H); 13C
NMR (125 MHz, CDCl3) d: 169.6, 144.0, 135.5, 133.7, 129.5,
129.4, 128.4, 124.6, 122.9, 118.3, 115.3, 78.4, 45.3, 24.3; MS
301, 127, 125; Anal. Calcd for C17H16ClNO2: C, 67.66; H,
5.34; N, 4.64. Found: C, 67.50; H, 5.33; N, 4.49%.
4-(Furan-2-ylmethyl)-2-methyl-2H-benzo[b][1,4]oxazin-3(4H)-
one (3db). Yellow solid; mp 82–84ꢁC; IR (KBr) 3115, 2987,
2864, 1680, 1600, 1502, 1394, 1273 cm-1; 1H NMR (500 MHz,
CDCl3) d: 7.35 (dd, J = 1, 2 Hz, 1H), 7.21–7.19 (m, 1H), 7.03–
6.99 (m, 3H), 6.32–6.29 (m, 2H), 5.16 (d, J = 16 Hz, 1H), 4.99
(d, J = 16 Hz, 1H), 4.64 (q, J = 7 Hz, 1H), 1.58 (d, J = 7 Hz,
3H); 13C NMR (125 MHz, CDCl3) d: 167.1, 150.2, 145.0,
142.6, 129.5, 124.4, 123.1, 117.7, 115.7, 111.0, 108.9, 73.9,
39.2, 16.7; MS 243, 134, 120, 81; Anal. Calcd for
C14H13NO3: C, 69.12; H, 5.39; N, 5.76. Found: C, 68.75; H,
5.40; N, 4.93%.
4-(Furan-2-ylmethyl)-2,2-dimethyl-2H-benzo[b][1,4]oxazin-
3(4H)-one (3dd). Light yellow solid; mp 47–49ꢁC; IR (KBr)
3115, 2983, 2929, 1680, 1597, 1502, 1463, 1390, 1259 cm-1;
1H NMR (500 MHz, CDCl3) d: 7.34 (dd, J = 1, 1.5 Hz, 1H),
7.14–7.11 (m, 1H), 7.01–6.95 (m, 3H), 6.31 (dd, J = 2, 3 Hz,
1H), 6.25 (d, J = 3 Hz, 1H), 5.08 (s, 2H), 1.51 (s, 6H); 13C
NMR (125 MHz, CDCl3) d: 169.1, 150.4, 143.8, 142.5, 129.5,
124.4, 122.7, 118.1, 115.2, 111.0, 108.5, 78.2, 39.3, 24.1; MS
257, 134, 120, 81; Anal. Calcd for C15H15NO3: C, 70.02; H,
5.88; N, 5.44. Found: C, 70.02; H, 5.87; N, 5.07%.
[5] (a) Matsumoto, Y.; Tsuzuki, R.; Matsuhisa, A.; Masuda, N.;
Yamagiwa, Y.; Yanagisawa, I.; Shibanuma, T.; Nohira, H. Chem Pharm
Bull 1999, 47, 971; (b) Piao, Z.-T.; Guan, L.-P.; Zhao, L.-M.; Piao,
H.-R.; Quan, Z.-S. Eur J Med Chem 2008, 43, 1216; (c) Sebille, S.;
de Tullio, P.; Boverie, S.; Antoine, M. H.; Lebrun, P.; Pirotte, B. Curr
Med Chem 2004, 11, 1213; (d) Caliendo, G.; Perissutti, E.; Santagada,
V.; Fiorino, F.; Severino, B.; di Villa Bianca, R.; Lippolis, L.; Pinto,
A.; Sorrentino, R. Bioorg Med Chem 2002, 10, 2663; (e) Fringuelli, R.;
Pietrella, D.; Schiaffella, F.; Guarraci, A.; Perito, S.; Bistoni, F.;
Vecchiarelli, A. Bioorg Med Chem 2002, 10, 1681; (f) Bromidge, S. M.;
Bertani, B.; Borriello, M.; Faedo, S.; Gordon, L. J.; Granci, E.; Hill, M.;
Marshall, H. R.; Stasi, L. P.; Zucchelli, V.; Merlo, G.; Vesentini, A.;
Watson, J. M.; Zonzini, L. Bioorg Med Chem Lett 2008, 18, 5653; (g)
Cheung, W. S.; Calvo, R. R.; Tounge, B. A.; Zhang, S. P.; Stone, D. R.;
Brandt, M. R.; Hutchinson, T.; Flores, C. M.; Player, M. R. Bioorg Med
Chem Lett 2008, 18, 4569; (h) Caliendo, G.; Perissutti, E.; Santagada, V.;
Fiorino, F.; Severino, B.; Cirillo, D.; d’Emmanuele di Villa Bianca, R.;
Lippolis, L.; Pinto, A.; Sorrentino, R. Eur J Med Chem 2004, 39, 815.
ꢀ
ꢀ
[6] (a) Ilas, J.; Jakopin, Z.; Borstnar, T.; Stegnar, M.; Kikelj, D. J
Med Chem 2008, 51, 5617; (b) La, D. S.; Belzile, J.; Bready, J. V.; Coxon,
A.; DeMelfi, T.; Doerr, N.; Estrada, J.; Flynn, J. C.; Flynn, S. R.; Graceffa,
R. F.; Harriman, S. P.; Larrow, J. F.; Long, A. M.; Martin, M. W.;
Morrison, M. J.; Patel, V. F.; Roveto, P. M.; Wang, L.; Weiss, M. M.;
Whittington, D. A.; Teffera, Y.; Zhao, Z.; Polverino, A. J.; Harmange, J.
C. J Med Chem 2008, 51, 1695; (c) Higuchi, R. I.; Arienti, K. L.; Lopez,
F. J.; Mani, N. S.; Mais, D. E.; Caferro, T. R.; Long, Y. O.; Jones, T. K.;
Edwards, J. P.; Zhi, L.; Schrader, W. T.; Negro-Vilar, A.; Marschke,
K. B. J Med Chem 2007, 50, 2486; (d) Schiaffella, F.; Macchiarulo, A.;
Milanese, L.; Vecchiarelli, A.; Costantino, G.; Pietrella, D.; Fringuelli,
R. J Med Chem 2005, 48, 7658; (e) Bourlot, A. S.; Sánchez, I.; Dureng,
G.; Guillaumet, G.; Massingham, R.; Monteil, A.; Winslow, E.; Pujol,
M. D.; Mérour, J. Y. J Med Chem 1998, 41, 314; (f) Achari, B.; Mandal,
S. B.; Dutta, P. K.; Chowdhury, Ch. Synlett 2004, 2449; (g) Fringuelli,
R.; Giacchè, N.; Milanese, L.; Cenci, E.; Macchiarulo, A.; Vecchiarelli,
A.; Costantino, G.; Schiaffella, F. Bioorg Med Chem 2009, 17, 3838; (h)
Macchiarulo, A.; Costantino, G.; Fringuelli, D.; Vecchiarelli, A.; Schiaffella,
F.; Fringuelli, R. Bioorg Med Chem Lett 2002, 10, 3415.
[7] (a) Feng, G.; Wu, J.; Dai, W.-M. Tetrahedron 2006, 62, 4635;
(b) Dai, W.-M.; Wang, X.; Ma, C. Tetrahedron 2005, 61, 6879; (c)
Matsumoto, Y.; Tsuzuki, R.; Matsuhisa, A.; Takayama, K.; Yoden, T.;
Uchida, W.; Asano, M.; Fujita, S.; Yanagisawa, I.; Fujikura, T. Chem
Pharm Bull 1996, 44, 103.
[8] (a) Lanni, T. B., Jr.; Greene, K. R.; Kolz, C. N.; Para, K. S.;
Visnick, M.; Mobley, J. L.; Dudley, D. T.; Baginski, T. J.; Liimatta, M.
B. Bioorg Med Chem Lett 2007, 17, 756; (b) Kluge, M.; Hartenstein, H.;
Hantschmann, A.; Sicker, D. J Heterocycl Chem 1995, 32, 395; (c)
Dudley, D. A.; Bunker, A. M.; Chi, L.; Cody, W. L.; Holland, D. R.;
Ignasiak, D. P.; Janiczek-Dolphin, N.; McClanahan, T. B.; Mertz, T. E.;
Narasimhan, L. S.; Rapundalo, S. T.; Trautschold, J. A.; Van Huis, C.
A.; Edmunds, J. J. J Med Chem 2000, 43, 4063; (d) Ma, Y.; Zhang, Y.
J Chem Res 2000, 388.
Ethyl 2-(2-(benzylamino)phenoxy)-2-methylpropanoate (3a0d).
1H NMR (500 MHz, CDCl3) d: 7.42–7.40 (m, 2H), 7.37–7.34
(m, 3H), 7.01–6.98 (m, 1H), 6.94–6.89 (m, 1H), 6.88–6.87 (m,
1H), 6.79 (dd, J = 1, 8 Hz, 1H), 5.17 (s, 1H), 4.41 (s, 2H), 4.26
(q, J = 7 Hz, 2H), 1.62 (s, 6H), 1.29 (t, J = 7 Hz, 3H); MS 313,
267, 198, 134, 91.
Acknowledgment. Iran National Science Foundation (INSF) is
gratefully acknowledged for financial support of this work
(Project 88000118).
[9] (a) Sharifi, A.; Salimi, R.; Mirzaei, M.; Abaee, M. S. Synth
Commun 2007, 37, 1825; (b) Abaee, M. S.; Mojtahedi, M. M.; Zahedi,
M. M.; Sharifi, R.; Khavasi, H. Synthesis 2007, 3339.
REFERENCES AND NOTES
[10] (a) Sharifi, A.; Abaee, M. S.; Tavakkoli, A.; Mirzaei, M.;
Zolfaghari, A. R. Synth Commun 2008, 38, 2958; (b) Abaee, M. S.;
Hamidi, V.; Mojtahedi, M. M. Ultrason Sonochem 2008, 15, 823; (c)
Mojtahedi, M. M.; Akbarzadeh, E.; Sharifi, R.; Abaee, M. S. Org Lett
2007, 9, 2791.
[1] (a) Wasserscheid, P.; Welton, T. Ionic Liquids in Synthesis;
Wiley-VCH: Weinheim, 2008; (b) Welton, T. Chem Rev 1999, 99,
2071; (c) Martins, M. A. P.; Frizzo, C. P.; Moreira, D. N.; Zanatta, N.;
Bonacorso, H. G. Chem Rev 2008, 108, 2015; (d) Le, Z.-G.; Chen,
Z.-C.; Hu, Y.; Zheng, Q.-G. J Heterocycl Chem 2005, 42, 735.
[11] Sharifi, A.; Barazandeh, M.; Abaee, M. S.; Mirzaei, M.
Tetrahedron Lett 2010, 51, 1852.
[2] (a) Rogers, R. D.; Seddon, K. Ionic Liquids: Industrial
Applications for Green Chemistry, ACS Series 818; Oxford University
[12] (a) Lee, C. L.; Chan, K. P.; Lam, Y.; Lee, S. Y. Tetrahedron
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

938
A. Sharifi, M. Barazandeh, M. S. Abaee, and M. Mirzaei
Vol 49
ꢀ
ꢀ
Lett 2001, 42, 1167; (b) Caliendo, G.; Grieco, P.; Perissutti, E.; Santagada,
V.; Santini, A.; Albrizio, S.; Fattorusso, C.; Pinto, A.; Sorrentino, R. Eur J
Med Chem 1998, 33, 957; (c) Tuerdi, H.; Chao, H. J.; Qiao, J. X.;
Wang, T. C.; Gungor, T. U.S. Patent 261,244, 2005; (c) Tuerdi, H.;
Chao, H. J.; Qiao, J. X.; Wang, T. C.; Gungor, T. Chem Abstr 2006,
144, 6677q.
J Org Chem 2003, 68, 7918; (b) Štefanic Anderluh, P.; Anderluh, M.; Ilas,
J.; Mravljak, J.; Sollner Dolenc, M.; Stegnar, M.; Kikelj, D. J Med Chem
2005, 48, 3110; (c) Štefanic, P.; Turnsek, K.; Kikelj, D. Tetrahedron 2003,
ꢀ
ꢀ
59, 7123.
[14] (a) Varma, R. S.; Namboodiri, V. V. Chem Commun 2001,
643; (b) Park, S.; Kazlauskas, R. J. J Org Chem 2001, 66, 8395; (c) Burrell,
A. K.; Del Sesto, R. E.; Baker, S. N.; McCleskey, T. M.; Baker, G. A.
Green Chem 2007, 9, 449.
[13] (a) Cho, S.-D.; Park, Y.-D.; Kim, J.-J.; Lee, S.-G.; Ma, C.;
Song, S.-Y.; Joo, W.-H.; Falck, J. R.; Shiro, M.; Shin, D.-S.; Yoon, Y.-J.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet