[Omim][BF4], a green and recyclable ionic liquid medium for the one-pot chemoselective synthesis of benzoxazinones

Article abstract of DOI:10.1016/j.tetlet.2010.01.122

An efficient procedure for the one-pot chemoselective synthesis of 2H-benzo[b][1,4]oxazin-3(4H)-one derivatives from their corresponding o-aminophenols is developed using DBU in the ionic liquid [omim][BF₄]. Upon completion of the reaction and separation of the product, the ionic liquid is recovered and successfully reused over nine recycles without any noticeable loss of performance.

Full text of DOI:10.1016/j.tetlet.2010.01.122

Tetrahedron Letters 51 (2010) 1852–1855
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
[Omim][BF4], a green and recyclable ionic liquid medium for the one-pot
chemoselective synthesis of benzoxazinones
*
Ali Sharifi , Mehdi Barazandeh, M. Saeed Abaee, Mojtaba Mirzaei
Chemistry and Chemical Engineering Research Center of Iran, PO Box 14335-186, Tehran, Iran
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient procedure for the one-pot chemoselective synthesis of 2H-benzo[b][1,4]oxazin-3(4H)-one
derivatives from their corresponding o-aminophenols is developed using DBU in the ionic liquid
[omim][BF4]. Upon completion of the reaction and separation of the product, the ionic liquid is recovered
and successfully reused over nine recycles without any noticeable loss of performance.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 30 November 2009
Revised 23 January 2010
Accepted 29 January 2010
Available online 4 February 2010
In line with increasing global environmental safety regulations,
ionic liquids (ILs) have gained significant attention as appropriate
media in various fields of chemistry.1,2 In particular, by alteration
of their cationic and anionic components, ILs with desired physical
and chemical properties can be tailored to boost the selectivity and
reactivity of various synthetic transformations.3,4 As a result, ILs
are very popular surrogates to the conventional organic solvents
due to their ease of recovery, very low vapor pressure, increased
thermal stability, ability to dissolve a wide range of organic com-
pounds and long shelf lives.5,6
2H-Benzo[b][1,4]oxazin-3(4H)-ones (3) have been the subject
of extensive research in synthetic7,8 and medicinal organic chemis-
try.9–15 Heterocycles 3 contribute to the structure of many impor-
tant biologically active natural and synthetic compounds.16–23 In
the majority of methods, ring closure of o-aminophenols or
clo[5.4.0]undec-7-ene (DBU) (Scheme 1). The procedure presents
a one-pot reaction which is mild, involves a broad range of starting
materials, takes place at room temperature and offers the possibil-
ity to recycle the IL efficiently.
The initial reactions of o-aminophenol (1a) with ethyl 2-bromo-
propionate (2a), conducted to optimize the conditions, are summa-
rized in Table 1. Among various carbonate bases used in
[omim][BF4]37 as the IL (entries 1–3), Cs2CO3 showed the best per-
formance (12 h reaction time) and selectively gave the desired
product 3aa in 80% yield (entry 3). NaHCO3 (entry 4), KF (entry
5) and CsF (entry 6) were unable to induce significant formation
of 3aa. In the search for other mild bases to convert efficiently
the starting materials to 3aa, we next examined the effect of sev-
eral amines in the reaction (entries 7–10), where DBU exhibited
the best performance producing 3aa in 93% yield after 2 h (entry
11). When the reaction was conducted in the absence of the IL (en-
try 12), no formation of 3aa was noticed even after 24 h. Alterna-
tively, omission of DBU also led to no detectable quantities of the
product after the same time period (entry 13) illustrating the cru-
cial roles of both the IL and DBU in the reaction. Other ILs were pre-
pared38,39 and used as the reaction medium (entries 14–21)
leading to lower yields of 3aa after 2 h.
o-nitrophenols with appropriately
a-substituted carbonyl com-
pounds or their synthetic equivalents have served as the main
routes for the syntheses of 3.24 Typically, o-aminophenols are eas-
ier starting materials to work with and their reactions do not
require the extra step of nitro group reduction associated with
the use of o-nitrophenols.25–28 A significant contribution towards
the one-pot synthesis of products 3 was made by Dai et al. using
microwave irradiation.29,30 Nevertheless, many of the o-aminophe-
nol annulation methods either require multi-step reactions, in-
volve heating at high temperatures, lead to low or moderate
yields of products, are limited to electron-rich reactants or demand
the use of the commercially unavailable starting materials. On the
basis of our studies on heterocyclic systems,31–33 and in continua-
tion of our previous investigations on the development of environ-
mentally friendly procedures,34–36 we report here our preliminary
results obtained on the IL-mediated annulation of o-aminophenols
1 with 2-bromoalkanoates 2 in the presence of 1,8-diazabicy-
Next, the optimized conditions ([omim][BF4]/DBU) were em-
ployed to examine the generality of the procedure (Table 2).40
R'
R
Br
O
HO
R'
OEt
IL, DBU, r.t.
+
R
O
N
Z
R"HN
Z
X
X
O
R"
2a: R=H, R'=Me
2b: R=H, R'=H
2c: R=Me, R'=Me
1a: Z=CH, X=H, R"=H
3
1b: Z=CH, X=4-Me, R"=H
1c: Z=CH, X=4-Cl, R"=H
1d: Z=CH, X=4-NO2, R"=H
1e: Z=CH, X=H, R"=CH2Ph
1f: Z=N, X=H, R"=H
* Corresponding author. Tel.: +98 21 44580720; fax: +98 21 44580762.
E-mail address: sharifi@ccerci.ac.ir (A. Sharifi).
Scheme 1.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.01.122

A. Sharifi et al. / Tetrahedron Letters 51 (2010) 1852–1855
1853
Table 1
Optimization of the reaction conditions for the synthesis of 3aa
100
80
60
40
20
0
Entry
Conditions
Time (h)
Yielda (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
[omim][BF4]/Na2CO3
[omim][BF4]/K2CO3
[omim][BF4]/Cs2CO3
[omim][BF4]/NaHCO3
[omim][BF4]/KF
[omim][BF4]/CsF
[omim][BF4]/Et3N
[omim][BF4]/pyridine
[omim][BF4]/DABCO
[omim][BF4]/DBN
[omim][BF4]/DBU
DBU
[omim][BF4]
[bmim][BF4]/DBU
[opy][BF4]/DBU
[bpy][BF4]/DBU
[omim]Cl/DBU
24
24
12
24
24
24
24
24
24
2
10
20
80
0
0
10
18
0
0
1
2
3
4
5
6
7
8
9
10
0
Number of cycles
85
93
0
2
Figure 1. Efficient recycling of the catalyst.
24
24
2
2
2
2
2
2
2
0
80
85
81
80
82
79b
71
59
phenol 1b also gave the expected products 3ba–bb in short time
periods (entries 3 and 4). Interestingly, aminophenols bearing elec-
tron-withdrawing groups, which in many cases are reported to un-
dergo cyclization with much lower efficiency,41,42 behaved equally
well under the optimized conditions, giving high yields of the
respective products in slightly longer times (entries 5–8).
In all cases, the reactions were completed rapidly at room
temperature and the products were easily separated by extraction
with Et2O. The IL was recovered and reused in the subsequent reac-
tions without significant loss of activity as shown in 10 consecutive
reactions of 1a with 2a (Fig. 1).
A comparison of the results with previous related investiga-
tions24–30 clearly verifies the superiority of the current method,
where both primary and secondary 2-bromoalkanoates react to
give high yields of benzoxazinones in short time periods. This
encouraged us to further investigate the applicability of the proce-
dure in engaging less reactive substrates. For example, there is very
limited precedence for one-pot annulations of o-aminophenols
[omim][NO3]/DBU
[bmim]Cl/DBU
[bmim][NO3]/DBU
[omim][PF6]/DBU
2
a
Isolated yield.
Reaction conducted at 50 °C.
b
Table 2
[Omim][BF4] mediated synthesis of benzoxazinones
Entry
Product
Time (h)
2
Yielda (%)
93
O
3aa
3ab
1
O
O
O
O
O
O
O
O
N
H
O
with 2-bromoalkanoates bearing tertiary carbons at their
a posi-
2
3
4
5
6
7
8
1
86
88
87
84
83
78
73
tion (i.e., 2c). Such substrates usually give moderate to low yields
of products using either high temperature reactions43 or step-wise
procedures.24,44 Another less reactive group of substrates are N-al-
kyl substituted o-aminophenols which require high temperatures
(conventional or microwave) and mixtures of solvents to give good
or moderate quantities of products.29 As shown in Table 3, both
types of the starting materials underwent cyclization reactions.
Reactions of sterically hindered 2c with 1a–d rapidly gave benzox-
azinones 3ac–dc in high yields (entries 1–4). Similar results were
N
H
O
3ba
3bb
3ca
0.5
1
N
H
O
N
H
O
Table 3
1.5
2
[Omim][BF4] mediated reactions of less reactive substrates
N
H
O
Cl
Entry
Product
Time (h)
Yielda (%)
94
O
3cb
3da
1
2
3ac
3bc
3cc
N
H
O
Cl
O
O
N
H
O
2
N
H
O
NO2
2
3
4
1
94
95
91
N
H
O
2.5
3db
NO2
N
H
2.5
3
O
O
N
H
Cl
a
Isolated yield.
O
3dc
NO2
Reactions of unsubstituted o-aminophenol (1a) with 2-bromoalk-
anoates 2a and 2b, gave high yields of products within 1–2 h
(entries 1 and 2). Electron-releasing p-methyl-substituted amino-
N
H
(continued on next page)

1854
A. Sharifi et al. / Tetrahedron Letters 51 (2010) 1852–1855
able loss of activity. The generality of the reaction and its efficient
Table 3 (continued)
engagement of electron-deficient o-aminophenols and sterically
hindered 2-bromoalkanotes make it an interesting and useful addi-
tion to the present methods. Similar annulation of o-aminothio-
phenols and phenylenediamines with various acceptors is
currently under investigation in our laboratory.
Entry
5
Product
Time (h)
Yielda (%)
O
3ea
3eb
8
93b
O
O
N
Ph
Ph
Acknowledgements
O
N
B. Mirmashhoori, F. Faraji and G. Khanalizadeh are thanked for
conducting some of the spectroscopic analyses.
6
7
7
95b
Supplementary data
O
N
Supplementary data (Spectra of new compounds) associated
with this article can be found, in the online version, at
doi:10.1016/j.tetlet.2010.01.122.
3ec
12
92b
O
Ph
References and notes
O
8
9
3fb
3fc
1.5
2
80
94
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X
EtOH
Figure 2. Suggested mechanism of the reaction.

A. Sharifi et al. / Tetrahedron Letters 51 (2010) 1852–1855
1855
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for the appropriate length of time. After completion of the reaction, based on
TLC monitoring, the reaction mixture was extracted with Et2O (3 Â 10 mL). The
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chromatography using silica gel and EtOAc/hexanes as eluent, if necessary. The
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50 °C for 1 h using a rotary evaporator) and reused in subsequent reactions.
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identity was confirmed by comparison of their spectroscopic data with those
available in the literature. New products were characterized by 1H NMR, 13C
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