A simple and expedient method for the stepwise synthesis of 2-ethoxy-(4H)-3,1-benzoxazine-4-ones

Article abstract of DOI:10.1016/j.cclet.2012.01.028

A simple and practical route is described for the synthesis of 2-ethoxy-(4H)-3,1-benzoxazine-4-ones using the coupling reaction of anthranilic acid derivatives with diethyl dicarbonate following with fast cyclization of the carbamate adduct with a dehydro

Full text of DOI:10.1016/j.cclet.2012.01.028

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Chinese Chemical Letters 23 (2012) 434–437
www.elsevier.com/locate/cclet
A simple and expedient method for the stepwise synthesis
of 2-ethoxy-(4H)-3,1-benzoxazine-4-ones
*
Asrin Bahmani, Mahnaz Sharafi-Kolkeshvandi, Farzad Nikpour
Department of Chemistry, Faculty of Sciences, University of Kurdistan, P.O. Box 66315-416, Sanandaj, Iran
Received 15 November 2011
Available online 4 March 2012
Abstract
A simple and practical route is described for the synthesis of 2-ethoxy-(4H)-3,1-benzoxazine-4-ones using the coupling reaction
of anthranilic acid derivatives with diethyl dicarbonate following with fast cyclization of the carbamate adduct with a
dehydrocyclization agent such as cyanuric chloride and N,N0-dicyclohexylcarbodiimide in PEG at room temperature. High yields
of the products obtained under mild reaction conditions with simple work-up of the reaction mixture.
# 2012 Farzad Nikpour. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
Keywords: 2-Ethoxy-(4H)-3,1-benzoxazine-4-ones; Diethyl dicarbonate; Cyanuric chloride; N,N0-Dicyclohexylcarbodiimide; Dehydrocyclization
reagent
2-Substituted 4H-3,1-benzoxazin-4-one and its derivatives are used directly or indirectly in many clinical
applications [1]. Because of the electronically unsaturated character of 4H-3,1-benzoxazinones, they are not
satisfactorily stable rings. Thus, one of the most important features in 4H-3,1-benzoxazinones chemistry is their use as
key starting materials for further transformations in design and synthesis of biologically active compound [2,3]. The
chemistry of 2-substituted (4H)-3,1-benzoxazin-4-ones has been reviewed by Coppola [4].
Although there are many methods for the synthesis of 2-amino- and 2-alkylthio-(4H)-3,1-benzoxazine-4-ones [4a],
however, few synthetic routes have ever been reported for 2-alkoxy substituents such as 2-ethoxy-(4H)-3,1-
benzoxazin-4-ones with most being, limited in substrate scope [5,6]. The most accessible method for the synthesis of
2-alkoxy-(4H)-3,1-benzoxazine-4-ones has been proved to be the one based on the coupling reaction of anthranilic
acid with alkyl chloroformate [7,9]. A dehydrative cyclization agent such as alkyl chloroformates, acetic anhydride,
concentrated sulfuric acid, thionyl chloride and phosphorus oxychloride has been used to effect the cyclization of the
produced carbamates [4a]. However, many of these methods have drawbacks or limitations such as the use of
expensive and very toxic reagents, harsh reaction conditions, unsuitable for sensitive substituents on aromatic ring and
produce of low to moderate yields of 2-ethoxybenzoxazin-4-ones. Herein, a practical, fast and convenient protocol for
the synthesis of the title compounds is described. For the first step, we used diethyl dicarbonate in place of ethyl
chloroformate. It is readily available, more stable than ethyl chloroformate and in reaction with a nucleophile such as
anthranilic acid derivatives eliminates a molecule of CO2 and EtOH which are green compounds. In the second step,
* Corresponding author.
E-mail address: fnikpour@uok.ac.ir (F. Nikpour).
1001-8417/$ – see front matter # 2012 Farzad Nikpour. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
doi:10.1016/j.cclet.2012.01.028

A. Bahmani et al. / Chinese Chemical Letters 23 (2012) 434–437
435
O
O
R1
R1
R1
O
N
R2
R3
COOH
NH2
EtO
O
2
OEt
R2
R3
TCT/Et3N or DCC
PEG/rt
COOH
R2
R3
O
O
PEG/rt
N
H
OEt
OEt
1
3
4
Scheme 1.
N,N0-dicyclohexylcarbodiimide (DCC) and 2,4,6-trichloro[1,3,5]triazine (cyanuric chloride, TCT) [10] were used as
dehydrocyclization agent in PEG. They are significantly easier to handle and simple to use in organic synthesis in
comparison with the mentioned dehydrocyclization agents. They have been used in benzoxazin-4-ones synthesis
previously; however, the reaction conditions or the results are not satisfactory. For example, TCTwas used under reflux
conditions in toluene during very long reaction times [11] and low to moderate yields obtained using DCC in pyridine
[5]. All of the reaction processes were carried out at room temperature and in PEG as an excellent green solvent
(Scheme 1).
The results show that anthranilic acid derivatives react readily with diethyl dicarbonate and the produced
carbamates cyclize clicky [12] with DCC or TCT in PEG. The reaction conditions are mild without need to use of any
catalyst and with simple work-up of the reaction mixture. Also, this method could be utilized for the synthesis of a
variety of substituents on aromatic ring. Results are summarized in Table 1.
As it is observed in Table 1, electron-donating groups increase the coupling reaction rate probably because they
increase the nucleophile strength; however, electron-withdrawing substituents decrease the rate of carbamate
formation. In the case of 1g, the 5-OH substituent reacts with diethyl dicarbonate in the same reaction conditions
employed. Thus, the produced EtO-CO-O group decreases the rate of carbamate formation. We observed no
substituent effects on the rate of dehydrocyclization. Besides, Table 1 shows that TCT gives higher yields of the
desired benzoxazine-4-ones 4 in comparison with DCC probably because of easier work-up of 4 from the reaction
mixture when TCT is used. The plausible mechanism is proposed in Scheme 2.
It is reasonable to assume that carbamates of 3 are produced by nucleophilic attack of anthranilic acids 1 to diethyl
dicarbonate. In the second step, the reaction seems to proceed through the nucleophilic attack of the carboxyl oxygen 3
to the cyclization reagent and formation of the intermediates 5 (Path A) or through the carbamate carbonyl oxygen to
TCT and formation of the intermediates 6 and 7 (Path B) which undergo a fast cyclization reaction to produce the
desired benzoxazine-4-one 4 with the elimination of living group. Since the conversion of the carboxyl OH to a good
living group is more common way, the pathway A is the more liable route for carrying out and progression of the
reaction.
The identification and characterization of the products were carried out by their physical and spectroscopic data
[13] and comparison of them with those of authentic samples. In IR spectra, C O and C N stretching bands were
observed in about 1780–1745 cmꢀ1 and 1650–1630 cmꢀ1, respectively. In the case of 4g the carbonate C O stretching
Table 1
Synthesis of 4 from the reaction of anthranilic acids 1a–g with diethyl dicarbonate and dehydrocyclization reaction of carbamates 3 with DCC or
TCT in PEG-400 at room temperature.
1
R1
R2
R3
Time (h)a
Yield 3 (%)b
Yield 4 (%)c
Yield 4 (%)d
a
b
c
d
e
f
H
H
H
1.5
0.5
0.5
4
85
90
90
85
80
80
85e
81
85
85
77
70
70
84e
90
90
85
80
90
82
80e
H
OMe
H
OMe
H
Me
H
Cl
H
H
Br
H
H
4
H
Cl
H
4
g
H
OH
3
a
b
c
d
e
For preparation of 3.
Isolated yields.
Isolated yields with DCC.
Isolated yields with TCT.
R2: EtO-CO-O.

436
A. Bahmani et al. / Chinese Chemical Letters 23 (2012) 434–437
Scheme 2.
band was observed in about 1730 cmꢀ1. The appearance of C4-carbon peak in about 158–156 ppm in 13C NMR is a
good reason for the formation of benzoxazine-4-one ring. In all cases molecular ion peaks with good to high
abundances appear in mass-spectral.
In conclusion, we have reported an expedient and highly efficient method for the synthesis of various substituents of
2-ethoxy-(4H)-benzoxazin-4-ones under mild reaction conditions. The coupling reaction of anthranilic acid
derivatives with diethyl dicarbonate following with dehydrocyclization of the produced carbamates with TCTor DCC
in PEG, leads to the desired benzoxazin-4-ones. This protocol, especially when TCT is used as cyclodehyrating
reagent, provides a practical alternative to the existing available methods for the synthesis of 2-ethoxy-(4H)-
benzoxazin-4-ones as an important class of pharmacological active compounds. Some notable advantages of this
procedure are the use of PEG as green solvent, the use of simple and available reagents, mild reaction conditions, click
dehydrocyclization reaction process without need to use of any catalyst and simplicity of all of the reaction steps which
produces high yields of the products with simple work-up of the reaction mixture.
Acknowledgment
We are thankful to the University of Kurdistan Research Council for the partial support of this work.
References
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[4] (a) G.M. Coppola, J. Heterocycl. Chem. 37 (2000) 1369;
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[5] S. Leistner, R. Simon, G. Wagner, J. Sturze-Becher, Pharmazie 42 (1987) 694.
[6] W. Kantlehner, T. Maier, W. Loffler, et al. Liebigs Ann. Chem. (1982) 507.
[7] M. Gutschow, U. Neumann, Bioorg. Med. Chem. 5 (1997) 1935.
[8] (a) A. Krants, R.W. Spencer, T.F. Tam, T.J. Liak, U.S. Patent, 4,745,116 (1988); Chem. Abstr. 109 (1988) 170447.
(b) A. Krantz, R.W. Spencer, T.F. Tam, et al. J. Med. Chem. 33 (1990) 464.
[9] C. Mitsos, A. Zografos, O. Lgglessi-Markopoulou, Heterocycles 51 (1999) 1543.
[10] G. Blotny, Tetrahedron 62 (2006) 9507.
[11] M.S. Khajavi, S.M. Shariat, Heterocycles 65 (2005) 1159.
[12] Click chemistry is a chemical philosophy and describes chemistry tailored to generate substances quickly. See: (a) H.C. Kolb, M.G. Finn, K.B.
Sharpless, Angew. Chem. Int. Ed. 40 (2001) 2004; (b) C.R. Becer, R. Hoogenboom, U.S. Schubert, Angew. Chem. Int. Ed. 48 (2009) 4900.
[13] Melting points were measured with an Electrothermal 9100 apparatus. IR spectra were measured with a Shimadzu IR-460 spectrometer. NMR
spectra were recorded with a Bruker DRX-250 AVANCE instrument (250.1 MHz for 1H and 62.9 MHz for 13C). Chemical shifts are given in
ppm (d) relative to internal TMS, and coupling constants J are reported in Hz. Mass spectra were recorded with a Agilent-5975C mass
spectrometer operating at an ionization potential of 70 eV. PEG with molecular weight 400 was used in all reactions. General reaction
procedure: Step 1: In a 25 mL round flask, an anthranilic acid derivative 1 (3 mmol) was dissolved in PEG-400 (1.5 mL) and then diethyl
dicarbonate (4.5 mmol) was added dropwise (in the case of 1g, 7 mmol diethyl dicarbonate was used). The reaction mixture was stirred at room
temperature for the times as indicated in Table 1. After of completion of the reaction, the residual of diethyl dicarbonate was removed under

A. Bahmani et al. / Chinese Chemical Letters 23 (2012) 434–437
437
reduced pressure. The carbamates 3 were washed with cold water and dried in air. Step 2: TCTas dehydrocyclization reagent: In a 25 mL round
flask, a mixture of a carbamate derivative 3 (1 mmol), TCT (1 mmol), triethylamine (1 mmol) and PEG-400 (0.5 mL) was stirred at room
temperature. The reaction was completed immediately. The mixture was washed with cold water (three times) and dried in air. The
benzoxazine-4-ones 4 may be recrystallized from n-hexane/THF, if needed. Step 2: DCC as dehydrocyclization reagent: In a 25 mL round
flask, a mixture of a carbamate derivative 3 (1 mmol), DCC (1 mmol), triethylamine (1 mmol) and PEG-400 (0.5 mL) was stirred at room
temperature. The reaction was completed immediately. The mixture was poured onto cold water and extracted with CHCl3. The organic layer
was separated, dried over MgSO4, and then, the solvent was removed under reduced pressure. The benzoxazine-4-ones 4 may be recrystallized
from n-hexane/THF, if needed. 2-Ethoxy-(4H)-3,1-benzoxazine-4-one (4a): White solid, mp: 87–89 8C (Lit. 88–90 8C) [6,8]. 2-Ethoxy-6,7-
dimethoxy-(4H)-3,1-benzoxazine-4-one (4b): White solid, mp: 164–166 8C (Lit. 155–156 8C) [5,8a]. IR (KBr): y (cmꢀ1) = 1747 (C O), 1630
(C N). 1H NMR (250 MHz in CDCl3): d 7.37 (s, 1H–Ar), 6.80 (s, 1H–Ar), 4.43 (q, 2H, 3JHH = 6.7 Hz, CH2), 3.95 and 3.90 (2s, 6H, OCH3),
1.41 (t, 3H, 3JHH = 6.7, CH3). 13C NMR (62.5 MHz in CDCl3): d 159.3, 156.7, 154.5, 147.7, 144.8, 107.8, 106.4, 106.3, 65.7, 56.4, 56.2, 14.0.
EI-MS (70 eV): m/z (%) 251 (M+ꢁ, 100). 2-Ethoxy-5-methyl-(4H)-3,1-benzoxazine-4-one (4c): White solid, mp: 102–104 8C (Lit. 104–105 8C)
[5,8a]. 6-Chloro-2-ethoxy-(4H)-3,1-benzoxazine-4-one (4d): white solid, mp: 83–85 8C. IR (KBr): y (cmꢀ1) = 1778 (C O), 1638 (C N). 1H
NMR (250 MHz in CDCl3): d 7.98 (s, 1H–Ar), 7.60 (d, 3JHH = 8.5 Hz, 1H–Ar), 7.31 (d, 3JHH = 8.5 Hz, 1H–Ar), 4.48 (q, 2H, 3JHH = 7.0 Hz,
CH2), 1.43 (t, 3H, 3JHH = 7.0 Hz, CH3). 13C NMR (62.5 MHz in CDCl3): d 158.4, 154.6, 146.8, 136.9, 131.1, 128.0, 126.8, 115.4, 66.3, 14.0.
EI-MS (70 eV): m/z (%) 225 (M+ꢁ, 56), 227 [(M+ꢁ + 2), 18]. 6-Bromo-2-ethoxy-(4H)-3,1-benzoxazine-4-one (4e): White solid, mp: 85–87 8C
(Lit. 87–89 8C) [5]. 7-Chloro-2-ethoxy-(4H)-3,1-benzoxazine-4-one (4f): White solid, mp: 80–82 8C. IR (KBr): y (cmꢀ1) = 1780 (C O), 1622
3
4
3
(C N). 1H NMR (250 MHz in CDCl3): d 7.99 (d, JHH = 8.5 Hz, 1H–Ar), 7.37 (d, JHH = 1.5 Hz, 1H–Ar), 7.26 (dd, JHH = 8.5 Hz,
4JHH = 1.5 Hz, 1H–Ar), 4.49 (q, 2H, 3JHH = 7.2 Hz, CH2), 1.43 (t, 3H, 3JHH = 7.2 Hz, CH3). 13C NMR (62.5 MHz in CDCl3): d 158.7, 155.3,
149.4, 143.1, 130.1, 126.4, 125.1, 112.7, 66.4, 14.0. EI-MS (70 eV): m/z (%) 225 (M+ꢁ, 38), 227 [(M+ꢁ + 2), 13]. 2-Ethoxy-6-(ethyl carbonato)-
(4H)-3,1-benzoxazine-4-one (4g): White solid, mp: 69–71 8C. IR (KBr): y (cmꢀ1) = 1772 (C O), 1732 (C O), 1633 (C N). 1H NMR
(250 MHz in CDCl3): d 8.43 (s, 1H–Ar), 7.72 (d, 3JHH = 7.5 Hz, 1H–Ar), 7.44 (d, 3JHH = 7.5 Hz, 1H–Ar), 4.33-4.22 (m, 4H, 2CH2), 1.45–1.32
(m, 6H, 2CH3). 13C NMR (62.5 MHz in CDCl3): d 158.6, 154.6, 154.5, 140.2, 139.8, 132.5, 126.0 (2C), 118.2, 63.7, 63.5, 14.6, 14.0. EI-MS
(70 eV): m/z (%) 279 (M+ꢁ, 16).