Palladium-catalyzed, microwave-assisted synthesis of 3,4-dihydro-3-oxo-2 H -1,4-benzoxazines: An improved catalytic system and multicomponent process

Article abstract of DOI:10.1055/s-0033-1338508

An improved palladium-catalyzed system is established for the synthesis of 3,4-dihydro-3-oxo-2H-1,4-benzoxazines from less reactive ethyl 2-(2-chlorophenoxy)alkanoates and aryl amines under controlled microwave heating, employing 2-dicyclohexylphosphino-2′,4′,6′- triisopropylbiphenyl (XPhos) as the ligand. Moreover, a high-yielding, three-component reaction protocol is disclosed for the efficient one-pot synthesis of 3,4-dihydro-3-oxo-2H-1,4-benzoxazines from 2-halophenols, ethyl 2-bromoalkanoates, and aryl amines. Microwave heating at high temperature is necessary to achieve high yields with 2-chlorophenol. A wide range of substrates is tolerated affording the desired products in good to excellent yields.

Full text of DOI:10.1055/s-0033-1338508

PAPER
▌2711
paper
Palladium-Catalyzed, Microwave-Assisted Synthesis of 3,4-Dihydro-3-oxo-
2H-1,4-benzoxazines: An Improved Catalytic System and Multicomponent
Process
Synthesis of 3,4-Dihydro-3-oxo-2H-1,4-benzoxazines
Gaofeng Feng,* Shengnan Wang, Weiting Li, Fengjiang Chen, Chenze Qi*
Zhejiang Key Laboratory of Alternative Technologies for Fine Chemicals Process, Shaoxing University, Shaoxing 312000, P.R. of China
Fax +86(575)88345682; E-mail: chfeng@usx.edu.cn; E-mail: qichenze@usx.edu.cn
Received: 02.05.2013; Accepted after revision: 27.06.2013
heterocyclic skeleton,6 which is often present in bioactive
Abstract: An improved palladium-catalyzed system is established
natural products.7 A variety of approaches have been es-
for the synthesis of 3,4-dihydro-3-oxo-2H-1,4-benzoxazines from
tablished to access this heterocyclic system.8 These in-
less reactive ethyl 2-(2-chlorophenoxy)alkanoates and aryl amines
under controlled microwave heating, employing 2-dicyclohex-
clude, amongst others, the use of 2-aminophenols9 or 2-
ylphosphino-2′,4′,6′-triisopropylbiphenyl (XPhos) as the ligand. nitrophenols10 as starting materials, a copper–palladium-
catalyzed tandem O-alkylation–amidation sequence,11
Moreover, a high-yielding, three-component reaction protocol is
disclosed for the efficient one-pot synthesis of 3,4-dihydro-3-oxo-
palladium-catalyzed intramolecular O-arylation,12 and a
2H-1,4-benzoxazines from 2-halophenols, ethyl 2-bromoalkano-
tandem Ugi four-component Mitsunobu cyclization.13
ates, and aryl amines. Microwave heating at high temperature is
However, a common limitation of these approaches was
necessary to achieve high yields with 2-chlorophenol. A wide range
the adoption of a stepwise synthetic sequence, which had
a dramatic influence on the synthetic efficiency. More-
over, in the corresponding metal-catalyzed protocols,
only aryl iodides and bromides were employed,11a,b,12 and
we found that aryl chlorides provided the desired products
in far lower yields due to their poor reactivity.11c We pre-
viously disclosed an efficient one-pot synthesis of 3,4-di-
hydro-3-oxo-2H-1,4-benzoxazines employing an Ugi
four-component reaction sequence, followed by base-
mediated O-alkylation.14 However, this procedure was
stepwise and the substitution diversity was limited. We
have also reported that 2-alkyl-4-aryl-3,4-dihydro-3-oxo-
2H-1,4-benzoxazines 1 could be synthesized efficiently
from ethyl 2-(2-halophenoxy)alkanoates 2 and aryl
amines through a sequence involving palladium–(±)-2,2′-
bis(diphenylphosphino)-1,1′-binaphthalene [(±)-BINAP]
catalyzed intermolecular amination and spontaneous ther-
mal intramolecular amidation (Scheme 1).15 This protocol
had three disadvantages: 1) the starting ethyl 2-(2-halo-
phenoxy)alkanoates 2 had to be prepared in advance from
2-halophenols 3 and ethyl 2-bromoalkanoates 4 in N,N-di-
methylformamide in the presence of potassium carbonate
(K2CO3), which had a dramatic influence on the synthetic
efficiency; 2) when ethyl 2-(2-chlorophenoxy)alkanoates
were employed, only a moderate yield (up to 45%) could
be achieved;15 3) the reaction time was long (up to 24 h).
Therefore, a more efficient protocol for accessing 3,4-di-
hydro-3-oxo-2H-1,4-benzoxazines 1 is desirable.
of substrates is tolerated affording the desired products in good to
excellent yields.
Key words: multicomponent reactions, microwave irradiation,
palladium-catalyzed,
cascade process
3,4-dihydro-3-oxo-2H-1,4-benzoxazines,
Diversity-oriented synthesis of small organic molecules
with biological activity is a technique of great value for
drug discovery.1 With the development of high-through-
put screening technology,2 the efficient preparation of li-
braries of analogues of bioactive small molecules is
possible. Hence, the search for novel strategies to improve
synthetic efficiency and increase structural variation is
very important in organic synthesis. For such purposes,
multicomponent reactions (MCRs)3 are recognized as
valuable tools, as they can incorporate a large degree of
diversity into molecular scaffolds, from simple and readi-
ly available building blocks, in a single synthetic step.
Moreover, multicomponent procedures do not necessitate
the isolation of intermediates, and introduce all or most of
the atoms originating from three or more starting materi-
als into the newly formed products, making the strategy
significantly more efficient and economic compared to
their multistep alternatives. Furthermore, both synthetic
efficiency and yield can be improved greatly by using
microwave irradiation,4 particularly for transition-metal-
catalyzed transformations. Thus, the development of new,
metal-catalyzed multicomponent reactions under micro-
wave irradiation for accessing privileged heterocycles has
attracted the attention of synthetic chemists.5
It is well known that the ligand plays a central role in pal-
ladium-catalyzed transformations. Thus we continued our
research on this palladium-catalyzed cascade process with
a ligand screen, and employing ethyl 2-(2-chlorophe-
noxy)acetate (2a) and 4-methylaniline as model sub-
strates. In order to improve the synthetic efficiency,
controlled microwave heating at high temperature
(150 °C) was employed. The results are listed in Table 1.
Palladium(II) acetate [Pd(OAc)2] and (±)-BINAP were
employed as the precatalyst and ligand, respectively. Af-
We are interested in the 3,4-dihydro-3-oxo-2H-1,4-benz-
oxazine scaffold as it represents a privileged, drug-like,
SYNTHESIS 2013, 45, 2711–2718
Advanced online publication: 01.08.2013
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0033-1338508; Art ID: SS-2013-F0312-OP
© Georg Thieme Verlag Stuttgart · New York

2712
G. Feng et al.
PAPER
O
Ar-NH2, Pd(OAc)2
R1
O
R1
O
O
X
(
)-BINAP, Cs2CO3
OH
K2CO3
DMF
OEt
OEt
R1
Br
+
N
toluene, oil bath
90 °C, 24 h
X
O
Ar
3
X = I, Br
4
2
1
O-alkylation step
Pd-catalyzed cascade sequence
Scheme 1 Our previously reported strategy toward 2-alkyl-4-aryl-3,4-dihydro-3-oxo-2H-1,4-benzoxazines 1
ter heating a mixture of 2a and 4-methylaniline in toluene ployed, the corresponding benzoxazine 1f was obtained in
under microwave heating at 150 °C for 1.5 hours, the de- 92% yield (Table 2, entry 5). In addition, the reaction of
sired product, 3,4-dihydro-4-(4-methylphenyl)-3-oxo- 4-trifluoromethoxyaniline and 1-naphthylamine with eth-
2H-1,4-benzoxazine (1a) was obtained in a low 28% yield yl 2-(2-chlorophenoxy)acetate (2a) afforded the corre-
(Table 1, entry 1). To our delight, when the ligand was re- sponding products 1g and 1h (Table 2, entries 6 and 7) in
placed with 2-dicyclohexylphosphino-2′,4′,6′-triisopro- 90% and 93% yields, respectively. Interestingly, reaction
pylbiphenyl (XPhos), the yield was improved greatly, of 3-aminopyridine gave the desired product 1i in 91%
affording 1a in an excellent 95% yield (Table 1, entry 2). yield (Table 2, entry 8).
Two other bidentate phosphine ligands were investigated
(Xantphos and dppf), but neither was as efficient as
XPhos (Table 1, entries 3 and 4).
At this stage, we had established an improved catalytic
system for synthesizing 3,4-dihydro-3-oxo-2H-1,4-benz-
oxazines 1 from ethyl 2-(2-chlorophenoxy)acetate (2a),
via controlled microwave heating in a significantly short-
er reaction time of 1.5 hours. However, two synthetic
Table 1 Optimization of the Ligand for the Synthesis of 3,4-Di-
hydro-4-(4-methylphenyl)-3-oxo-2H-1,4-benzoxazine (1a) under
Microwave Heatinga
steps were required to obtain the target molecule. We en-
visaged that it might be possible to perform the O-alkyla-
tion step and the subsequent palladium-catalyzed cascade
sequence in one-pot to establish a three-component pro-
cess from 2-halophenols 3, ethyl 2-bromoalkanoates 4,
and aryl amines 5, since only a base and solvent were
needed for both steps (Scheme 2). If successful, the syn-
thetic efficiency would be greatly improved. To the best
of our knowledge, there have been no prior reports on a
multicomponent approach for accessing 2-alkyl-4-aryl-
3,4-dihydro-3-oxo-2H-1,4-benzoxazines.
O
N
NH2
O
O
cat., ligand
O
OEt
+
MW, 150 °C, 1.5 h
Cl
2a
1a
Entry
Ligand (mol%)
Yield (%)b
1
2
3
4
(±)-BINAP (10)
XPhos (20)
28
95
71
13
R1
OH
X
O
R1
O
Pd, ligand, base
solvent, MW
Xantphos (10)
dppf (10)
OEt
+
+
Ar-NH2
Br
N
O
Ar
4
5
1
3
a Reaction conditions: ethyl 2-(2-chlorophenoxy)acetate (2a) (0.3
mmol), 4-methylaniline (0.45 mmol), Pd(OAc)2 (10 mol%), ligand,
Cs2CO3 (0.6 mmol), toluene (4 mL), MW, 150 °C, 1.5 h.
b Yield of isolated product.
X = I, Br, Cl
Scheme 2 A multicomponent strategy for the synthesis of 2-alkyl-4-
aryl-3,4-dihydro-3-oxo-2H-1,4-benzoxazines 1
We reasoned that the key to the success of the multicom-
ponent process would be the compatibility of both condi-
tions. Therefore, conditions for both the O-alkylation and
palladium-catalyzed cascade process were further investi-
gated. As shown in Scheme 3, the reaction of ethyl 2-(2-
iodophenoxy)acetate (2b) with 4-methylaniline in toluene
in the presence of palladium(II) acetate, XPhos and
Cs2CO3 afforded the desired product, 4-(4-methylphe-
nyl)-3,4-dihydro-3-oxo-2H-1,4-benzoxazine (1a) in 91%
yield under microwave irradiation at 150 °C for one hour.
However, N,N-dimethylformamide was not a good sol-
vent for this palladium-catalyzed cascade process as the
yield decreased to 64%. To our delight, the use of toluene
as the solvent and cesium carbonate (Cs2CO3) as the base
led to smooth O-alkylation of 2-iodophenol with ethyl 2-
bromoacetate, under microwave heating at 100 °C for 30
minutes, to furnish the acetate 2b in 85% yield.
Next, the generality of this more powerful catalytic sys-
tem was investigated using anilines containing different
substituents (Table 2). The reaction of ethyl 2-(2-chloro-
phenoxy)acetate (2a) and 3,5-dimethylaniline proceeded
smoothly under the optimized conditions, affording the
desired product 1b in an excellent 95% yield (Table 2, en-
try 1). Anilines containing electron-withdrawing groups
(CO2Et, CF3 and CN) tolerated these conditions, provid-
ing the corresponding products 1c–e in 87%, 93% and
81% yields, respectively (Table 2, entries 2–4). Notably,
when a mixture of 2a and 4-trifluoromethylaniline was
heated in an oil bath at 100 °C for 17 hours, the desired
product was obtained in a slightly lower yield of 88%, in-
dicating that microwave heating at higher temperature de-
creased the reaction time. Also, the reaction was
compatible with an aniline containing an electron-donat-
ing group. For example, when 4-methoxyaniline was em-
Synthesis 2013, 45, 2711–2718
© Georg Thieme Verlag Stuttgart · New York

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Synthesis of 3,4-Dihydro-3-oxo-2H-1,4-benzoxazines
2713
Table 2 Synthesis of 3,4-Dihydro-4-aryl-3-oxo-2H-1,4-benzoxa-
zines 1 via the Microwave-Assisted, Palladium-Catalyzed Cascade
Processa (continued)
Table 2 Synthesis of 3,4-Dihydro-4-aryl-3-oxo-2H-1,4-benzoxa-
zines 1 via the Microwave-Assisted, Palladium-Catalyzed Cascade
Processa
O
O
O
O
NH2
NH2
Pd(OAc2), XPhos
Pd(OAc2), XPhos
O
O
Cs2CO3, MW
Cs2CO3, MW
N
O
N
O
+
OEt
2a
+
OEt
2a
R
R
Y
Y
150 °C, 1.5 h
150 °C, 1.5 h
1
1
Cl
Cl
R
R
Y
Y
Y = CH, N
Y = CH, N
Entry
8
Product
Yield (%)b
Entry
1
Product
Yield (%)b
O
N
O
N
O
O
1i
91
1b
95
N
a Reaction conditions: ethyl 2-(2-chlorophenoxy)acetate (2a) (0.3
mmol), aryl amine (0.54 mmol), Pd(OAc)2 (10 mol%), XPhos (20
mol%), Cs2CO3 (1.05 mmol), toluene (4.0 mL), MW, 150 °C, 1.5 h.
b Yield of isolated product.
O
N
O
2
3
1c
87
c Reaction run in an oil bath at 100 °C for 17 h.
COOEt
O
O
NH2
O
N
O
Pd(OAc)2, XPhos, Cs2CO3
O
I
N
O
+
93 (88)c
OEt
1d
MW, 150 °C, 1 h
toluene: 91%
DMF: 64%
1a
2b
CF3
O
O
OH
I
N
O
O
O
O
I
Cs2CO3, toluene
OEt
OEt
+
Br
4
5
1e
1f
81
92
MW, 100 °C, 30 min
85%
O
2b
CN
O
Scheme 3 Investigation of the palladium-catalyzed cascade process
and O-alkylation under microwave heating
N
Having established the best solvent and base, the catalyst,
ligand, temperature, reaction time, and catalyst loading
for this three-component reaction were optimized using 2-
iodophenol, ethyl 2-bromoacetate, and 4-methylaniline as
model substrates. The results are summarized in Table 3.
Inspired by the preliminary results obtained for the O-al-
kylation and palladium-catalyzed cascade processes un-
der microwave heating, a stepwise heating approach was
adopted. Thus, on heating a mixture of 2-iodophenol, eth-
yl 2-bromoacetate, and 4-methylaniline in the presence of
palladium(II) acetate (10 mol%), XPhos (20 mol%), and
cesium carbonate in toluene at 100 °C for 30 minutes, and
then at 150 °C for one hour, the desired product, 4-(4-
methylphenyl)-3,4-dihydro-3-oxo-2H-1,4-benzoxazine
(1a) was isolated in 35% yield (Table 3, entry 1). Gratify-
ingly, extending the reaction time to 90 minutes at 100 °C
and then two hours at 150 °C, respectively, resulted in an
improved 63% yield, along with a 31% yield of the inter-
mediate, ethyl 2-(2-iodophenoxyl)acetate (2b) (Table 3,
OMe
O
N
6
7
1g
1h
90
93
OCF3
O
N
O
© Georg Thieme Verlag Stuttgart · New York
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G. Feng et al.
PAPER
entry 2). Further extending the reaction time and using Table 4. Three 2-halophenols (X = I, Br, Cl), three ethyl
higher loadings of palladium(II) acetate (15 mol%) and 2-bromoalkanoates 4 (R1 = H, Me, Et), and various aryl
XPhos (30 mol%) led to a 95% yield of the product (Table amines were examined. We found that 2-iodophenol, 2-
3, entry 3). Reducing the loadings of palladium(II) acetate bromophenol, and even the much less reactive 2-chloro-
and XPhos to 12 mol% and 24 mol%, respectively, did not phenol were compatible, indicating that microwave heat-
affect the yield (94%, Table 3, entry 4). Despite the excel- ing at high temperature was beneficial for the process.
lent yield, a total reaction time of five hours was required. Aryl amines including 4-methylaniline, aniline, and 3,5-
Pleasingly, direct heating of the reaction mixture at dimethylaniline tolerated the reaction conditions, afford-
150 °C for three hours led to an excellent 96% yield of 1a ing the corresponding products 1a, 1m, and 1b in excel-
(Table 3, entry 5). Lowering the catalyst and ligand load- lent yields, ranging from 92–96% (Table 4, entries 1–3).
ings to 10 mol% and 20 mol%, respectively, resulted in a Moreover, the conditions were compatible with anilines
slightly reduced 92% yield (Table 3, entry 6). However, bearing both electron-withdrawing (4-CO2Et and 4-CF3)
further reducing the loadings of the catalyst and ligand to and electron-donating (4-OMe) groups, furnishing the
5 mol% and 10 mol%, respectively, gave only a 36% yield corresponding products 1c, 1d, and 1f in excellent 78–
of 1a (Table 3, entry 7). Three bidentate phosphine li- 97% yields (Table 4, entries 4–6). The reaction of 4-tri-
gands [(±)-BINAP, Xantphos, dppf] were screened, but fluoromethoxyaniline, 2-halophenols, and ethyl 2-bromo-
none of these proved to be as efficient as XPhos (Table 3, acetate proceeded smoothly, affording the benzoxazine 1g
entries 8–10). Finally, palladium(II) chloride (PdCl2) and in yields of 88–93% (Table 4, entry 7). With bulky 1-
tris(dibenzylideneacetone)dipalladium(0)
[Pd2(dba)3] naphthylamine, slightly lower yields (78–84%) were ob-
were investigated as precatalysts. Palladium(II) chloride tained (Table 4, entry 8). Interestingly, when bulkier
was not a good choice as only a 64% yield of product 1a methyl 2-bromopropanoate was employed (Table 4, entry
was obtained (Table 3, entry 11). On the other hand, 9), the yield decreased dramatically to 46%. However, a
tris(dibenzylideneacetone)dipalladium(0) proved to be an slightly improved yield of 56% was achieved when the re-
effective precatalyst providing the desired product in 93% action mixture was first heated at 100 °C for two hours,
yield (Table 3, entry 12).
and then at 150 °C for three hours. In contrast, reaction of
more hindered ethyl 2-bromobutanoate did not afford the
desired heterocycle 1k, although the O-alkylation prod-
With optimized conditions in hand, the generality of the
process was investigated and the results are presented in
Table 3 Optimization of the Three-Component Approacha
O
NH2
OH
I
N
O
Pd, ligand, Cs2CO3
toluene, MW
OEt
Br
+
+
O
1a
Entry
Catalyst (mol%)
Ligand (mol%)
Conditions (MW)
Yield (%)b
1
2
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (15)
Pd(OAc)2 (12)
Pd(OAc)2 (12)
Pd(OAc)2 (10)
Pd(OAc)2 (5)
Pd(OAc)2 (12)
Pd(OAc)2 (12)
Pd(OAc)2 (12)
PdCl2 (12)
XPhos (20)
XPhos (20)
XPhos (30)
XPhos (24)
XPhos (24)
XPhos (20)
XPhos (10)
(±)-BINAP (12)
Xantphos (12)
dppf (12)
100 °C, 0.5 h, then 150 °C, 1 h
100 °C, 1.5 h, then 150 °C, 2 h
100 °C, 2 h, then 150 °C, 3 h
100 °C, 2 h, then 150 °C, 3 h
150 °C, 3 h
35
63c
95
94
96
92
36
42
27
13
64
93
3
4
5
6
150 °C, 3 h
7
150 °C, 3 h
8
150 °C, 3 h
9
150 °C, 3 h
10
11
12
150 °C, 3 h
XPhos (24)
XPhos (24)
150 °C, 3 h
Pd2(dba)3 (6)
150 °C, 3 h
a Reaction conditions: 2-iodophenol (0.3 mmol), ethyl 2-bromoacetate (0.45 mmol), 4-methylaniline (0.54 mmol), Pd catalyst, ligand, Cs2CO3
(1.05 mmol), toluene (4.0 mL), MW heating.
b Yield of isolated product.
c Ethyl 2-(2-iodophenoxyl)acetate (2b) was isolated in 31% yield.
Synthesis 2013, 45, 2711–2718
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Synthesis of 3,4-Dihydro-3-oxo-2H-1,4-benzoxazines
2715
Table 4 Three-Component Synthesis of 3,4-Dihydro-3-oxo-2H-1,4-
uct, ethyl 2-(2-bromophenoxy)butanoate, was isolated in
70% yield (Table 4, entry 10). These two results indicated
that the three-component process was sensitive to the size
of the ethyl 2-bromoalkanoate input, which was inconsis-
tent with our previously reported palladium-catalyzed,
two-component process.15 Interestingly, when 4-chloro-
aniline was employed, the unexpected dehalogenated
product, 3,4-dihydro-4-phenyl-3-oxo-2H-1,4-benzoxa-
zine (1m), instead of the desired benzoxazine 1l, was ob-
tained as the only heterocyclic product in a very low yield
of 27% (Table 4, entry 11). As a result of the high reactiv-
ity of our catalytic system, which promotes the coupling
reaction of aryl chlorides, most of the initially formed
product 1l would further react with excess 4-chloroaniline
to give oligomeric materials. The dechlorinated by-prod-
uct 1m would be formed via protonolysis of the palladi-
um(II) intermediate derived from oxidative addition of 1l
to palladium(0).
benzoxazines under Microwave Heatinga
O
N
R1
O
NH2
R1
Pd(OAc)2, XPhos
Cs2CO3
OH
X
OEt
Br
+
+
O
toluene, MW, 150 °C
3 h
R2
5
3: X = I, Br, Cl
4
1
R2
Entry
Product
Yield (%)
O
N
O
X = Br (96)
X = Cl (93)
1
1a
O
N
The advantages of microwave heating over conventional
heating for this three-component reaction were also exam-
ined. Thus, reactions of 2-iodophenol, 2-bromophenol,
and 2-chlorophenol with ethyl 2-bromoaceate and 4-
methylaniline were carried out in an oil bath at 100 °C for
14 hours. The expected product 1a was obtained in 98%,
88%, and 26% yields (Scheme 4). These results show that
microwave heating at high temperature was essential to
achieve high yields with 2-chlorophenol and thereby im-
prove the synthetic efficiency.
O
O
O
X = Br (96)
X = Cl (92)
2
3
1m
1b
O
N
X = I (94)
O
N
X = I (89)b
X = Cl (97)
O
NH2
4
5
6
1c
1d
1f
OH
OEt
+
Pd(OAc)2, XPhos, Cs2CO3
Br
N
O
+
O
X
toluene, oil bath, 100 °C, 14 h
CO2Et
O
X = I: 98%
X = Br: 88%
X = Cl: 26%
3a–c
4a
1a
X = I (95)b
X = Br (84)
X = Cl (85)
N
O
Scheme 4 Synthesis of 3,4-dihydro-4-(4-methylphenyl)-3-oxo-2H-
1,4-benzoxazine (1a) via the three-component reaction in an oil bath
CF3
O
In summary, an efficient palladium-catalyzed procedure
has been developed for accessing 3,4-dihydro-3-oxo-2H-
1,4-benzoxazines from less reactive ethyl 2-(2-chlorophe-
nyl)alkanoates and amines. The use of XPhos as the li-
gand was found to be crucial for enhanced catalytic
activity. In addition, a one-pot, three-component approach
has been established for the efficient synthesis of the tar-
get heterocycles from 2-halophenols, ethyl 2-bromoal-
kanoates, and aryl amines. It was found that microwave
heating at high temperature had significant advantages in
terms of improving the synthetic efficiency and achieving
high yields compared to conventional heating, particular-
ly with 2-chlorophenol as one of the substrates. The re-
ported protocol tolerates a broad range of substrates,
provides high yields of the desired products, and should
be attractive for the synthesis of libraries of 3,4-dihydro-
3-oxo-2H-1,4-benzoxazines.
N
O
X = I (94)
X = Br (78)
X = Cl (95)
OMe
O
X = I (88)b
X = Br (93)
X = Cl (89)
N
O
7
8
1g
1h
OCF3
O
X = I (79)
X = Br (84)
X = Cl (78)
N
O
© Georg Thieme Verlag Stuttgart · New York
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G. Feng et al.
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Table 4 Three-Component Synthesis of 3,4-Dihydro-3-oxo-2H-1,4-
kanoate (0.45 mmol), an aryl amine (0.54 mmol), Cs2CO3 (1.05
mmol), Pd(OAc)2 (6.7 mg, 0.03 mmol, 10 mol%), and XPhos (28.5
mg, 0.06 mmol, 20 mol%). The vial was then sealed with a silicon
cap, evacuated and back-filled with N2 through the cap (this proce-
dure was repeated several times), and anhyd degassed toluene (4
mL) was added via a syringe (through the cap). The resulting mix-
ture was heated at 150 °C for 3 h under microwave irradiation. After
cooling, the mixture was filtered through Celite and the filter-bed
was rinsed with EtOAc. The filtrate was concentrated under re-
duced pressure and the residue purified by column chromatography
on silica gel [EtOAc–PE (60–90 °C)] to afford the corresponding
3,4-dihydro-3-oxo-2H-1,4-benzoxazine. The yields of the products
are given in Table 4.
benzoxazines under Microwave Heatinga (continued)
O
N
R1
O
NH2
R1
Pd(OAc)2, XPhos
Cs2CO3
OH
X
OEt
Br
+
+
O
toluene, MW, 150 °C
3 h
R2
5
3: X = I, Br, Cl
4
1
R2
Entry
Product
Yield (%)
O
N
3,4-Dihydro-4-(4-methylphenyl)-3-oxo-2H-1,4-benzoxazine
(1a)11a
Yield: 68.8 mg (96%); white crystalline solid.
1H NMR (400 MHz, CDCl3): δ = 7.35 (d, J = 8.0 Hz, 2 H), 7.19 (d,
J = 8.0 Hz, 2 H), 7.05 (dd, J = 8.0, 1.6 Hz, 1 H), 7.00 (ddd, J = 8.0,
8.0, 1.6 Hz, 1 H), 6.86 (ddd, J = 8.0, 8.0, 1.6 Hz, 1 H), 6.47 (dd,
J = 8.0, 1.6 Hz, 1 H), 4.79 (s, 2 H), 2.44 (s, 3 H).
O
O
O
X = I (46)
X = I (56)b
9
1j
O
N
3,4-Dihydro-4-(3,5-dimethylphenyl)-3-oxo-2H-1,4-benzoxa-
zine (1b)15
Yield: 71.3 mg (94%); yellowish amorphous solid.
1H NMR (400 MHz, CDCl3): δ = 7.11 (s, 1 H), 7.05 (dd, J = 8.0, 1.6
Hz, 1 H), 7.00 (ddd, J = 8.0, 8.0, 1.6 Hz, 1 H), 6.91 (s, 2 H), 6.87
(ddd, J = 8.0, 8.0, 1.6 Hz, 1 H), 6.47 (dd, J = 8.0, 1.2 Hz, 1 H), 4.78
(s, 2 H), 2.38 (s, 6 H).
10
11
1k
1l
X = Br (0)c
O
N
X = Br (0)d
3,4-Dihydro-4-(4-ethoxycarbonylphenyl)-3-oxo-2H-1,4-benz-
oxazine (1c)11a
Yield: 86.4 mg (97%); white crystalline solid.
1H NMR (400 MHz, CDCl3): δ = 8.23 (d, J = 8.4 Hz, 2 H), 7.40 (d,
J = 7.6 Hz, 2 H), 7.08 (d, J = 7.6 Hz, 1 H), 7.03 (dd, J = 8.0, 8.0 Hz,
1 H), 6.88 (dd, J = 7.6, 7.6 Hz, 1 H), 6.44 (d, J = 8.0 Hz, 1 H), 4.79
(s, 2 H), 4.43 (q, J = 6.8 Hz, 2 H), 1.43 (t, J = 6.8 Hz, 3 H).
Cl
a Reaction conditions: 2-halophenol (0.3 mmol), ethyl 2-bromoal-
kanoate (0.45 mmol), aryl amine (0.54 mmol), Pd(OAc)2 (10 mol%),
XPhos (20 mol%), Cs2CO3 (1.05 mmol), toluene (4.0 mL), MW,
150 °C, 3 h.
3,4-Dihydro-3-oxo-4-(4-trifluoromethylphenyl)-2H-1,4-benz-
oxazine (1d)11a
Yield: 83.5 mg (95%); white crystalline solid.
1H NMR (400 MHz, CDCl3): δ = 7.82 (d, J = 8.8 Hz, 2 H), 7.47 (d,
J = 8.4 Hz, 2 H), 7.10 (dd, J = 8.0, 1.6 Hz, 1 H), 7.05 (ddd, J = 8.0,
8.0, 1.2 Hz, 1 H), 6.92–6.88 (m, 1 H), 6.44 (dd, J = 8.0, 1.2 Hz, 1
H), 4.79 (s, 2 H).
b Microwave heating at 100 °C for 2 h, and then at 150 °C for 3 h.
c The intermediate, ethyl 2-(2-bromophenoxy)butanoate was isolated
in 70% yield.
d The dehalogenated product, 3,4-dihydro-4-phenyl-3-oxo-2H-1,4-
benzoxazine (1m), was obtained in 27% yield.
4-(4-Cyanophenyl)-3,4-dihydro-3-oxo-2H-1,4-benzoxazine (1e)
Yield: 60.7 mg (81%); yellowish solid; Rf = 0.45 (25% EtOAc–
hexane).
IR (KBr) 1686, 1498, 1372, 1299, 1058, 749 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.85 (d, J = 8.4 Hz, 2 H), 7.48 (d,
J = 8.8 Hz, 2 H), 7.10 (dd, J = 8.0, 2.0 Hz, 1 H), 7.06 (ddd, J = 8.0,
8.0, 1.6 Hz, 1 H), 6.92 (ddd, J = 8.0, 8.0, 1.6 Hz, 1 H), 6.44 (dd,
J = 8.0, 1.2 Hz, 1 H), 4.78 (s, 2 H).
13C NMR (100 MHz, CDCl3): δ = 164.2, 145.3, 140.1, 133.8, 129.8,
124.9, 122.9, 118.0, 117.5, 116.9, 112.6, 68.2.
MS (ESI+): m/z (%) = 251 (50) [M + H]+, 274 (100).
Reagents were obtained from commercial suppliers and were used
as received. The extent of reaction was monitored by thin-layer
chromatography on Yantai silica gel plates (60 F-254), and samples
were made visual using UV light or 7% ethanolic phosphomolybdic
acid with heating. Flash column chromatography was performed us-
ing Qingdao Haiyang silica gel (300–400 mesh). Yields refer to
chromatographically and spectroscopically (1H NMR) homoge-
neous materials. Reactions were heated using a Biotage Initiator 2.5
microwave reactor. IR spectra were obtained using a Nicolet 6700
FTIR spectrophotometer. 1H and 13C NMR spectra were recorded in
CDCl3 using a Bruker Avance III 400 spectrometer (400 MHz for
1H and 100 MHz for 13C, respectively) with residual CHCl3 as the
internal reference. Mass spectra (ESI+) were measured using
Thermo Fisher Scientific LCQ Sheet instrumentation. Elemental
analysis was performed using a Euro Vector EA3000 analyser.
Anal. Calcd for C15H10N2O2: C, 71.99; H, 4.03; N, 11.19. Found: C,
71.70; H, 4.27; N, 10.52.
3,4-Dihydro-4-(4-methoxyphenyl)-3-oxo-2H-1,4-benzoxazine
(1f)11a
Yield: 72.7 mg (95%); white crystalline solid.
1H NMR (400 MHz, CDCl3): δ = 7.22 (d, J = 8.4 Hz, 2 H), 7.07–
7.05 (m, 3 H), 7.00 (dd, J = 8.0, 8.0 Hz, 1 H), 6.87 (dd, J = 8.0, 8.0
Hz, 1 H), 6.48 (d, J = 8.4 Hz, 1 H), 4.78 (s, 2 H), 3.88 (s, 3 H).
Xantphos
= 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene;
dppf = 1,1′-bis(diphenylphosphino)ferrocene.
3,4-Dihydro-3-oxo-2H-1,4-benzoxazines 1; General Procedure
To a pressure-safe vial (10 mL) containing a magnetic stir bar were
added a 2-halophenol (0.3 mmol), an ethyl 2-(2-halophenoxy)al-
Synthesis 2013, 45, 2711–2718
© Georg Thieme Verlag Stuttgart · New York

PAPER
Synthesis of 3,4-Dihydro-3-oxo-2H-1,4-benzoxazines
2717
3,4-Dihydro-3-oxo-4-(4-trifluoromethoxyphenyl)-2H-1,4-
benzoxazine (1g)15
Min, J.; Kim, D. J.; Chang, Y.-T.; Hecht, M. H. ACS Chem.
Biol. 2006, 1, 461.
Yield: 86.2 mg (93%); yellow crystalline solid.
(3) (a) Li, M.; Lv, X.-L.; Wen, L.-R.; Hu, Z.-Q. Org. Lett. 2013,
15, 1262. (b) Huang, Y.; Khoury, K.; Chanas, T.; Dömling,
A. Org. Lett. 2012, 14, 5916. (c) Dömling, A.; Wang, W.;
Wang, K. Chem. Rev. 2012, 112, 3083. (d) Ruijter, E.;
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(b) Yu, C.-W.; Chen, G. S.; Huang, C.-W.; Chern, J.-W.
Org. Lett. 2012, 14, 3688. (c) Nguyen, H. H.; Kurth, M. J.
Org. Lett. 2013, 15, 362. (d) Kappe, C. O. Acc. Chem. Res.
2013, 46, in press; doi: 10.1021/ar300318c. (e) Loupy, A. In
Microwaves in Organic Synthesis; Wiley-VCH: Weinheim,
2002. (f) Kappe, C. O.; Pieber, B.; Dallinger, D. Angew.
Chem. Int. Ed. 2013, 52, 1088.
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Chem. 2013, 78, 4158. (b) Yang, D.; Burugupalli, S.; Daniel,
D.; Chen, Y. J. Org. Chem. 2012, 77, 4466. (c) Mehta, V. P.;
Modha, S. G.; Ruijter, E.; van Hecke, K.; van Meervelt, L.;
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Eycken, E. J. Org. Chem. 2011, 76, 2828. (d) Chebanov, V.
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Knyazeva, I. V.; Shishkina, S. V.; Shishkin, O. V.; Kappe,
C. O. J. Comb. Chem. 2006, 8, 427.
1H NMR (400 MHz, CDCl3): δ = 7.41–7.35 (m, 4 H), 7.08 (dd,
J = 8.0, 1.6 Hz, 1 H), 7.03 (ddd, J = 8.0, 8.0, 1.2 Hz, 1 H), 6.90 (ddd,
J = 8.0, 8.0, 2.0 Hz, 1 H), 6.45 (dd, J = 8.0, 1.2 Hz, 1 H), 4.79 (s, 2
H).
3,4-Dihydro-4-(naphth-1-yl)-3-oxo-2H-1,4-benzoxazine (1h)11c
Yield: 69.3 mg (84%); yellow crystalline solid.
1H NMR (400 MHz, CDCl3): δ = 8.00 (d, J = 8.0 Hz, 1 H), 7.96 (d,
J = 7.6 Hz, 1 H), 7.62 (d, J = 8.0 Hz, 2 H), 7.56–7.47 (m, 3 H), 7.11
(dd, J = 8.0, 1.2 Hz, 1 H), 6.99 (ddd, J = 8.0, 8.0, 1.2 Hz, 1 H), 6.76
(ddd, J = 8.0, 8.0, 1.2 Hz, 1 H), 6.23 (dd, J = 8.0, 1.2 Hz, 1 H), 4.91
and 4.84 (ABq, J = 15.2, 15.2 Hz, 2 H).
3,4-Dihydro-3-oxo-4-(3-pyridinyl)-2H-1,4-benzoxazine (1i)11a
Yield: 61.7 mg (91%); white solid.
1H NMR (400 MHz, CDCl3): δ = 8.71 (d, J = 4.4 Hz, 1 H), 8.59 (s,
1 H), 7.68 (ddd, J = 8.0, 2.0, 1.6 Hz, 1 H), 7.50 (dd, J = 8.0, 4.8 Hz,
1 H), 7.08 (dd, J = 8.0, 1.6 Hz, 1 H), 7.03 (ddd, J = 8.0, 8.0, 1.2 Hz,
1 H), 6.89 (ddd, J = 8.0, 8.0, 1.2 Hz, 1 H), 6.43 (dd, J = 8.0, 1.2 Hz,
1 H), 4.78 (s, 2 H).
3,4-Dihydro-2-methyl-4-(4-methylphenyl)-3-oxo-2H-1,4-benz-
oxazine (1j)11a
Yield: 42.5 mg (56%); white crystalline solid.
1H NMR (400 MHz, CDCl3): δ = 7.34 (d, J = 8.0 Hz, 2 H), 7.16 (d,
J = 8.0 Hz, 2 H), 7.05 (d, J = 7.6 Hz, 1 H), 6.99 (dd, J = 7.2, 7.2 Hz,
1 H), 6.86 (ddd, J = 8.0, 8.0, 1.2 Hz, 1 H), 6.45 (d, J = 8.0 Hz, 1 H),
4.81 (q, J = 6.8 Hz, 1 H), 2.44 (s, 3 H), 1.66 (d, J = 6.8 Hz, 3 H).
(6) (a) Sainsbury, M. Oxazines, Thiazines and their Benzo
Derivatives, In Comprehensive Heterocyclic Chemistry;
Vol. 3; Katritzky, A. R.; Rees, C. W., Eds.; Pergamon:
Oxford, 1984, 995–1038. (b) 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.;
Huis, C. A. V.; Edmunds, J. J. J. Med. Chem. 2000, 43, 4063.
(c) Caliendo, G.; Perissutti, E.; Santagada, V.; Fiorino, F.;
Severino, B.; d’Emmanuele di Villa Bianca, R.; Lippolis, L.;
Pinto, A.; Sorrentino, R. Bioorg. Med. Chem. 2002, 10,
2663. For recent reviews, see: (d) Sebille, S.; de Tullio, P.;
Boverie, S.; Antoine, M. H.; Lebrun, P.; Pirotte, B. Curr.
Med. Chem. 2004, 11, 1213. (e) Macias, F. A.; Marin, D.;
Oliveros-Bastidas, A.; Molinillo, J. M. G. Nat. Prod. Rep.
2009, 26, 478.
3,4-Dihydro-3-oxo-4-phenyl-2H-1,4-benzoxazine (1m)11a
Yield: 64.8 mg (96%); white crystalline solid.
1H NMR (400 MHz, CDCl3): δ = 7.58–7.54 (m, 2 H), 7.51–7.47 (m,
1 H), 7.32–7.30 (m, 2 H), 7.07 (dd, J = 8.0, 1.6 Hz, 1 H), 7.01 (ddd,
J = 8.0, 8.0, 1.2 Hz, 1 H), 6.87 (ddd, J = 8.0, 8.0, 1.6 Hz, 1 H), 6.45
(dd, J = 8.0, 1.2 Hz, 1 H), 4.80 (s, 2 H).
Acknowledgment
Financial support from Shaoxing University and the Science Tech-
nology Bureau of Shaoxing (2012B70020) is acknowledged. We
also thank the Education Department of Zhejiang province for sup-
port (Y201225961).
Supporting Information for this article is available online at
(7) (a) Minami, Y.; Yoshida, K.; Azuma, R.; Saeki, M.; Otani,
T. Tetrahedron Lett. 1993, 34, 2637. For designed
enediynes, see: (b) Dai, W.-M. Curr. Med. Chem. 2003, 10,
2265.
http://www.thieme-connect.com/ejournals/toc/synthesis.SnuIomprifgtooatrinSugpIoi
n
nfomartit
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Synthesis 2013, 45, 2711–2718
© Georg Thieme Verlag Stuttgart · New York