Guanidinum chloride as dehydrocyclization agent in the synthesis of 2-fuctionalized (4H)-3,1-benzoxazine-4-ones

Article abstract of DOI:10.1002/jhet.1649

A facile and expedient route for the synthesis of 2-ethoxy- and 2-(ethylcarboxylate)-(4H)-3,1-benzoxazine-4-ones is described using guanidinium chloride as a safe and convenient dehydrocyclization agent. High yields of the products obtain under mild react

Full text of DOI:10.1002/jhet.1649

34
Guanidinum Chloride as Dehydrocyclization Agent in the Synthesis of
Vol 51
2-Fuctionalized (4H)-3,1-Benzoxazine-4-ones
*
Farzad Nikpour, Asrin Bahmani, Forugh Havasi, and Mahnaz Sharafi-Kolkeshvandi
Department of Chemistry, Faculty of Sciences, University of Kurdistan, Pasdaran Blvd., P.O. Box: 66135-416, Sanandaj, Iran
*
E-mail: fnikpour@uok.ac.ir; farzad_nikpour@yahoo.com
Received November 4, 2011
DOI 10.1002/jhet.1649
Published online 7 October 2013 in Wiley Online Library (wileyonlinelibrary.com).
. HCl
NH
O
, PEG/Et3N
CO2H
H N
NH
2
2
O
R
N
H
N
R
X
X
O
80-93%
R = OEt, CO2Et
A facile and expedient route for the synthesis of 2-ethoxy- and 2-(ethylcarboxylate)-(4H)-3,1-benzoxazine-4-
ones is described using guanidinium chloride as a safe and convenient dehydrocyclization agent. High yields of
the products obtain under mild reaction conditions without need to use of any catalyst and with easy work-up of
the reaction mixture.
J. Heterocyclic Chem., 51, 34 (2014).
INTRODUCTION
RESULTS AND DISCUSSION
2-Functionalized (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 due to the susceptibil-
ity of the C-4 carbonyl to nucleophilic attack, they are not
satisfactorily stable rings. Especially, hetero substituents
and chemically active functional groups on C-2 position
affect the reactivity and the reaction rate of them. 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].
In general, 2-carbon-containing substituents and 2-alkoxy
(4H)-3,1-benzoxazine-4-ones are formed from the coupling
reaction of anthranilic acid derivatives with an acyl chloride
or alkyl chloroformate, and then, a dehydrative cyclization
agent such as ethyl chloroformate [5], acetic anhydride [6],
concentrated sulfuric acid [7], thionyl chloride [8], phospho-
rus oxychloride [9], dicyclohexylcarbodiimide (DCC) [9],
and cyanuric chloride [10] has been used to effect the cycli-
zation of the produced amides or carbamates. Although some
of these methods are useful, many of them have drawbacks
or limitations such as the use of expensive and very toxic
reagents, harsh reaction conditions, unsuitable for unstable
substituents on aromatic ring and produce of low to moderate
yields of the product. Thus, there is further scope to explore a
mild and efficient method for the synthesis of the title com-
pounds. No doubt, general effective methods to synthesize
or to modify the preparation of biologically active com-
pounds using nontoxic and simple molecules with different
functionalities are worthwhile effort in organic syntheses.
With the aim of extending synthetic methods and in
continuation of our recent work on the synthesis of 2-
(ethylcarboxylate)-(4H)-3,1-benzoxazine-4-ones [11], we
now focused our attention on the simple and safe methods
for dehydrocyclization reactions. Herein, a practical and
green protocol for the synthesis of some benzoxazine-4-
ones is described using guanidinium chloride [12] for the
first time as dehydrocyclization agent. It is significantly
easier to handle and safe to use in organic synthesis in
comparison with the mentioned ones. The results of
synthesis of 2-ethoxy-(4H)-3,1-benzoxazin-4-ones show
that carbamates 3 [13] dehydrocyclized clickly [14] in the
presence of guanidinium chloride without need to use of
any catalyst (Scheme 1). All of the reaction processes were
carried out in PEG as an excellent green solvent with easy
work-up of the reaction mixture. Also, this method could
be utilized for the synthesis of a variety of substituents on
aromatic rings. Results are summarized in Table 1.
As it is observed in Table 1, electron-donating groups
increase the formation rate of carbamate 3 probably
because they increase the nucleophile strength; however,
electron-withdrawing substituents decrease the coupling
reaction rate. We observed no substituent effects on the
rate of dehydrocyclization.
To emphasized the ability of guanidinium chloride as a
general dehydrative cyclization agent in organic syntheses,
we examined the preparation of ethyl 4-oxo-4H-benzo[d]
[1,3]oxazine-2-carboxylates 7 [11] from the amides 6.
The experiments showed that high yields of 7 obtained
under mild reaction conditions with easy work-up the
reaction mixture (Scheme 2). However, the reaction rates
are not click here and need 0.5–3 h for cyclization probably
© 2013 HeteroCorporation

January 2014 Guanidinum Chloride in the Synthesis of 2-Fuctionalized (4H)-3,1-Benzoxazine-4-ones
35
Scheme 1
NH . HCl
O
O
R1
R1
R1
O
N
R2
R3
COOH
NH2
H2N
NH2
EtO
O
OEt
R2
R3
COOH
R2
R3
4
2
O
O
N
PEG/Et3N/rt
PEG/rt
OEt
OEt
H
oxygen of carbamates 3 or amides 6 to guanidine and forma-
tion of the intermediate 8 (path A) or through the path B by
nucleophilic attack of the carbamate oxygen 3 or carbonyl
oxygen of the amides 6 to guanidine and formation of the
intermediates 9, which undergo a fast cyclization reaction to
produce the desired benzoxazine-4-one 5 or 7 with the elimi-
nation of a molecule of urea. Because the conversion of the
carboxyl OH to a good living group is fast and more common
in organic synthesis, pathway A is the more liable route for
carrying out and progression of the reaction.
The identification and characterization of products 5 and 7
were deduced from their physical and spectroscopic data and
comparison of them with those of authentic samples. In IR
spectra of 5, C═O and C═N stretching bands were observed
in about 1780–1745 cmÀ1 and 1650–1630 cmÀ1, respec-
tively. In the case of 5g, an additional C═O stretching was
observed in about 1730 cmÀ1 because of the carbonate
formation. The appearance of C4-carbon peak in about
156–158 ppm in 13C NMR is a good reason for the formation
of benzoxazine ring. In IR spectra of 7, lactone and ester CO-
stretching bands were observed in about 1770–1755 cmÀ1
and 1740–1725 cmÀ1, respectively. Also, these two carbonyl
groups appear in about 158–160 ppm in 13C NMR. In the
case of 13C NMR of 7g, two additional carbonyl groups
related to 6-substitution appeared at about 159 and
170 ppm. In all cases, molecular ion peaks with good to high
abundances appear in mass spectral.
Table 1
Synthesis of benzoxazin-4-ones 5 from the reaction of anthranilic acids 1a–g
with diethyl dicarbonate and dehydrocyclization reaction of carbamates 3
with guanidinium chloride in PEG-400 at room temperature.
Yield 3
Yield 5
1
R1
R2
H
R3
H
Time (h)a
(%)b
(%)b
a
b
c
d
e
f
H
H
Me
H
H
1.5
0.5
0.5
4
4
4
85
90
90
85
80
80
85c
85
93
90
86
88
90
92c
OMe OMe
H
Cl
Br
H
H
H
H
Cl
H
H
H
g
OH
3
aFor preparation of 3.
bIsolated yields.
cR2: EtO–CO–O.
because of more electron-withdrawing effect of the 2-ethyl
carcoxylate group that causes to reduce the nucleophilic
strength of carbonyl oxygen of the amide in cyclization
process (Scheme 3).
According to the obtained results and also based on
the severe inclination of guanidine to convert to urea by
absorption of water, the plausible mechanisms are
proposed for cyclization step in Scheme 3.
Although we made no attempts to characterize the produced
intermediates, it is reasonable to assume that the reaction
proceeds through the nucleophilic attack of the carboxyl
CONCLUSIONS
Scheme 2
This protocol provides a practical alternative to the
existing available methods for the synthesis of some 2-
functionalized (4H)-benzoxazin-4-ones as an important
class of clinical active compounds. The coupling reaction
of anthranilic acid derivatives with suitable reagents
following with dehydrocyclization of the produced carba-
mates or amides with guanidinium chloride leads to the
desired benzoxazin-4-ones. The notable advantages of this
procedure are the use of readily available and nontoxic
reagents and solvent especially the use of guanidinium
chloride for the first time as dehydrative cyclization agent
that causes cyclization reaction without need to use of any
catalyst. Also, mild reaction conditions and simplicity of all
R1
NH . HCl
R1
O
N
R2
R3
COOH
R2
R3
H2N
NH2
O
O
N
PEG/Et3N/60-70 o
C
CO2Et
CO2Et
H
6
7
R1
R2
R3
Time (h) Isolated yields 7 (%)
H
H
Me
H
H
H
H
OMe
H
Cl
Br
H
OMe
H
H
H
1.5
1.5
0.5
2.5
2.5
2
85
90
92
85
80
82
83
a
b
c
d
e
f
H
Cl
H
H
EtO2C-COO
g
3
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

36
F. Nikpour, A. Bahmani, F. Havasi, and M. Sharafi-Kolkeshvandi
Vol 51
Scheme 3
O
O
NH
NH2
O
O
Path A
O
O
N
R
N
H
-
X
X
R
H N
2
NH
2
.
NH
HCl
/ Et3N
5 or 7
CO2H
8
H2N
NH2
O
- Et3NHCl
- H3N
N
H
X
R
H
O
N
O
R = OEt, CO2Et
Path B
O
O
R
O
R
O
3 or 6
N
H
-
X
X
O
H N
2
NH
2
NH
H2N
H2N
NH
9
10
Synthesis of the amides 6. In a 25 mL round flask, a mixture
of 3 mmol of an anthranilic acid derivative 1a–g and 3.3 mmol
of triethylamine was stirred in CHCl3 at room temperature, and
then, 3.3 mmol of ethyl chloroformylformate (in the case of 1g,
6.5 mmol of Et3N and 6.5 mmol ethyl chloroformylformate) was
added dropwise to this solution, and the mixture was stirred in
an ice bath for about 30 min. The solvent was removed under
reduced pressure, and the precipitate was washed first with
3 mL of n-hexane (three times) and filtered to remove the
residual of ethyl chloroformylformate and then with cold water
(three times) to remove the Et3NHCl salt and dried in air.
Synthesis of the benzoxazine-4-ones 7. In a 25 mL round
flask, a mixture of 1 mmol of the amides 6, 1.1 mmol of
guanidinium chloride, 1.1 mmol of triethylamine, and 0.5 mL
PEG was stirred at 60–70ꢀC for the times as indicated in
Scheme 2. After completion of the reaction, the mixture was
washed first with cold water (three times) to remove the solvent,
Et3NHCl salt, and the residual of guanidinium chloride. The
raw products were washed with 5% aqueous NaHCO3 and then
with H2O and dried in air. They may be recrystallized from
n-hexane/EtOAc, if needed [11].
of the reaction steps cause to produce high yields of the
products with easy work-up of the reaction mixture.
Guanidinium chloride can be a general and suitable reagent
for many dehydrocyclization reactions in organic synthesis.
EXPERIMENTAL
Melting points were measured with an Electrothermal 9100 appa-
ratus (Rochford, UK). IR spectra were measured with a Shimadzu IR-
460 spectrometer (Kyoto, Japan). NMR spectra were recorded with a
Bruker DRX-250 AVANCE (Rheinstetten, Germany) 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 an Agilent-5975C
inert XL MSD mass spectrometer (USA) operating at an ionization
potential of 70 ev. Elemental analyses of C, H, and N were performed
using a Heraeus CHN-O-Rapid analyzer (Hanau, Germany). PEG
with molecular weight 400 was used in all reactions.
General reaction procedure.
Synthesis of the carbamates 3. In a 25 mL round flask,
3 mmol of an anthranilic acid derivative 1a–g was dissolved in
1.5 mL PEG, and then, 4.5 mmol of diethyl dicarbonate was
added dropwise (in the case of 1g, 7 mmol of diethyl
dicarbonate was used). The reaction mixture was stirred at room
temperature for the times as indicated in Table 1. After
completion of the reaction, the residual of diethyl dicarbonate
was removed under reduced pressure. The carbamates 3a–g
were washed with cold water and dried in air.
Synthesis of the benzoxazine-4-ones 5. In a 25 mL round
flask, a mixture of 1 mmol of the carbamates 3, 1.1 mmol of
guanidinium chloride, 1.1 mmol of triethylamine, and 0.5 mL
PEG was stirred at room temperature. The reaction was
completed immediately. The mixture was washed first with cold
water (three times) to remove the solvent, Et3NHCl salt, and the
residual of guanidinium chloride. The raw products were
washed with 5% aqueous NaHCO3 and then with H2O and
dried in air. The benzoxazine-4-ones 5 may be recrystallized
from n-hexane/THF, if needed.
2-Ethoxy-(4H)-3,1-benzoxazine-4-one (5a). White solid,
mp: 87–89ꢀC [7,9].
2-Ethoxy-6,7-dimethoxy-(4H)-3,1-benzoxazine-4-one
(5b). White solid, mp: 164–166ꢀC. IR (KBr): υ (cmÀ1):= 1747
(C═O), 1630 (C═N). 1H NMR (250.1 MHz in CDCl3):
d
(ppm) = 7.37 (s, 1H-Ar), 6.80 (s, 1H-Ar), 4.43 (q,
3JH3H = 6.7Hz, 2H, CH2), 3.95 and 3.90 (2s, 6H, OCH3), 1.41
(t, JHH = 6.7, 3H, CH3). 13C NMR (62.9 MHz in CDCl3): d
(ppm) = 159.3, 156.7, 154.5, 147.7, 144.8, 107.8, 106.4, 106.3,
65.7, 56.4, 56.2, 14.0. EIMS (70 eV): m/z (%) = 251 (M+Á, 100).
Anal. Calcd for C12H13NO5 (251.24): C, 57.37; H, 5.21; N,
5.57. Found: C, 57.40; H, 5.24; N, 5.59.
2-Ethoxy-5-methyl-(4H)-3,1-benzoxazine-4-one (5c). White
solid, mp: 102–104ꢀC [15].
6-Chloro-2-ethoxy-(4H)-3,1-benzoxazine-4-one (5d). White
solid, mp: 83–85ꢀC. IR (KBr): υ (cmÀ1) = 1778 (C═O), 1638
(C═N). 1H NMR (250.1 MHz in CDCl3): d (ppm) = 7.98 (s, 1H-Ar),
3
3
7.60 (d, JHH = 8.5Hz, 1H-Ar), 7.31 (d, JHH = 8.5Hz, 1H-Ar), 4.48
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

January 2014 Guanidinum Chloride in the Synthesis of 2-Fuctionalized (4H)-3,1-Benzoxazine-4-ones
37
3
3
(q, JHH = 7.0Hz, 2H, CH2), 1.43 (t, JHH = 7.0Hz, 3H, CH3). 13C
NMR (62.9 MHz in CDCl3): d (ppm) = 158.4, 154.6, 146.8, 136.9,
131.1, 128.0, 126.8, 115.4, 66.3, 14.0. EIMS (70 eV): m/z (%) = 225
(M+Á, 56), 227 [(M+ + 2), 18]. Anal. Calcd for C10H8ClNO3 (225.63):
C, 53.23; H, 3.57; N, 6.21. Found: C, 53.26; H, 3.56; N, 6.20.
6-Bromo-2-ethoxy-(4H)-3,1-benzoxazine-4-one (5e). White
solid, mp: 85–87ꢀC. IR (KBr): υ (cmÀ1) = 1766 (C═O), 1635
(C═N). 1H NMR (250.1MHz in CDCl3): d (ppm) = 8.21
Acknowledgments. We are thankful to the University of Kurdistan
Research Council for partial support of this work.
REFERENCES AND NOTES
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4
3
4
(d, JHH = 2.0 Hz, 1H-Ar), 7.78 (dd, JHH = 8.5Hz, JHH = 2.0 Hz,
3
3
1H-Ar), 7.29 (d, JHH = 8.5Hz, 1-Ar), 4.51 (q, JHH = 7.0 Hz, 2H,
CH2), 1.45 (t, JHH = 7.0Hz, 3H, CH3). 13C NMR (62.9MHz in
3
CDCl3): d (ppm) = 158.3, 155.0, 147.2, 139.8, 131.2, 127.0,
118.5, 115.9, 66.3, 14.0. EIMS (70 eV): m/z (%) = 269 (M+Á, 72),
271 [(M+ + 2), 71]. Anal. Calcd for C10H8BrNO3 (270.08):
C, 44.47; H, 2.98; N, 5.18. Found: C, 44.44; H, 2.97; N, 5.20.
7-Chloro-2-ethoxy-(4H)-3,1-benzoxazine-4-one (5f). White
solid, mp: 80–82ꢀC. IR (KBr): υ (cmÀ1) = 1780 (C═O), 1622
(C═N). 1H NMR (250.1MHz in CDCl3): d (ppm) = 7.99
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3
4
(d, JHH = 8.5Hz, 1H-Ar), 7.37 (d, JHH = 1.5Hz, 1H-Ar), 7.26
3
4
3
(dd, JHH = 8.5Hz, JHH = 1.5Hz, 1H-Ar), 4.49 (q, JHH = 7.2Hz,
2H, CH2), 1.43 (t, JHH = 7.2Hz, 3H, CH3). 13C NMR
3
(62.9 MHz in CDCl3): d (ppm) = 158.7, 155.3, 149.4, 143.1,
130.1, 126.4, 125.1, 112.7, 66.4, 14.0. EIMS (70eV): m/z
(%) = 225 (M+, 38), 227 [(M+Á + 2), 13]. Anal. Calcd for
C10H8ClNO3 (225.63): C, 53.23; H, 3.57; N, 6.21. Found: C,
53.27; H, 3.58; N, 6.20.
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2-Ethoxy-6-(ethylcarbonato)-(4H)-3,1-benzoxazine-4-one
(5g). White solid, mp: 69–71ꢀC. IR (KBr): υ (cmÀ1) = 1772 (C═O),
1732 (C═O), 1633 (C═N). 1H NMR (250.1 MHz in CDCl3): d
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chloroformate, and in reaction with a nucleophile such as anthranilic acid
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3
(ppm) = 8.43 (s, 1H-Ar), 7.72 (d, JHH = 7.5Hz, 1H-Ar), 7.44 (d,
3JHH = 7.5Hz, 1H-Ar), 4.33–4.22 (m, 4H, 2CH2), 1.45–1.32 (m,
6H, 2CH3). 13C NMR (62.9MHz in CDCl3): d (ppm) = 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. EIMS (70 eV): m/z (%) = 279 (M+Á, 16). Anal. Calcd for
C13H13NO6 (279.25): C, 55.91; H, 4.69; N, 5.02. Found: C, 55.96;
H, 4.70; N, 5.00.
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet