A Pd-catalyzed cascade protocol towards 2-alkyl-4-aryl-4H-benz[1,4]oxazin- 3-ones from aryl amines and 2-(2-halophenoxy)alkanoates

Article abstract of DOI:10.1055/s-0031-1290346

A cascade process, consisting of Pd-catalyzed intermolecular amination and subsequent thermal intramolecular amidation, has been established for efficient one-pot synthesis of 4H-benz[1,4]oxazin-3-ones from anilines and 2-(2-halophenoxy)alkanoates. Use of

Full text of DOI:10.1055/s-0031-1290346

LETTER
601
A Pd-Catalyzed Cascade Protocol towards 2-Alkyl-4-aryl-4H-benz[1,4]oxazin-
3-ones from Aryl Amines and 2-(2-Halophenoxy)alkanoates
4H
-Benz[1,4]oxa
z
a
in-3-ones fr
o
om
A
nilines
f
a
nd 2-(2
e
-
Halophen
n
oxy)alkanoat
g
es Feng,a Fangling Yin,b Fengjiang Chen,a Qingbao Song,b Chenze Qi*a
a
The Institute of Applied Chemistry, Shaoxing University, Shaoxing 312050, P. R. of China
College of Chemical Engineering and Material Science, Zhejiang University of Technology, Hangzhou 310027, P. R. of China
Fax +86(575)88345682; E-mail: qichenze@usx.edu.cn
b
Received 22 November 2011
our ongoing interest. We envisaged that 4H-benz[1,4]ox-
azin-3-one scaffold might be efficiently constructed from
2-(2-halophenoxy)alkanoates 3 and anilines 2 in the pres-
ence of Pd catalyst through a sequence of intermolecular
Abstract: A cascade process, consisting of Pd-catalyzed intermo-
lecular amination and subsequent thermal intramolecular amida-
tion, has been established for efficient one-pot synthesis of 4H-
benz[1,4]oxazin-3-ones from anilines and 2-(2-halophenoxy)al-
kanoates. Use of Cs2CO3 as the base was found to be determinant amination and spontaneous lactamization under heating
for the process and alkyl groups attached to the a position of al-
kanoates are beneficial for achieving good yields. Various sub-
strates were compatible to afford the desired products in good to
excellent yields. It is an attractive process for synthesizing a library
of 4H-benz[1,4]oxazin-3-ones.
(Scheme 1). Although the tandem process seems feasible,
there are two unique challenges: (1) the oxidative addition
in the amination step may be difficult due to alkoxy group
at the ortho position of the aryl bromide; and (2) the lac-
tamization of the N-arylaniline product may be hampered
when R2 is an electron-withdrawing group, which can re-
duce the nucleophilicity of nitrogen atom. Herein, we re-
port our original investigations on the Pd-catalyzed
cascade process, consisting of intermolecular amination
and spontaneous lactamization, for efficient synthesis of
2-alkyl-4-aryl-4H-benz[1,4]oxazin-3-ones.
Key words: cascade reaction, palladium catalysis, amination, 4H-
benz[1,4]oxazin-3-ones, lactamization
A great deal of naturally occurring and synthetic derivates
of 4H-benz[1,4]oxazin-3-one 1 exhibit potent biological
and medicinal activities,1 thus its synthesis has attracted
the attention of synthetic chemists.2 So far, four novel
strategies have been developed for their preparation2–6
(Scheme 1): (a) O-alkylation of 2-nitrophenols, followed
by nitro group reduction and spontaneous annulation;3 (b)
regioselective N-acylation of 2-aminophenols with 2-ha-
loalkanoyl chlorides or bromides, followed by intramo-
lecular O-alkylation;4 (c) intermolecular O-alkylation and
Cu-catalyzed intramolecular amidation sequence from 2-
halophenols and 2-halo amides;5 and (d) a simple Pd-cat-
alyzed intramolecular O-arylation of the corresponding
precursor.6 From the synthetic points of view, these meth-
ods are inconvenient for the synthesis of 4H-benz[1,4]-
oxazin-3-ones, as stepwise synthetic sequences were
adopted. Therefore, the development of an alternative or
an improved procedure towards this heterocycle is still in
demand.
OH
OH
R1
R1
(b)
NH2
NO2
(a)
R1
O
N
R2
O
R3
1
(c)
(d)
O
OH
Br
Cl
R2
R1
O
+
R1
N
H
OH
X
N
ref. 5
R3
R2
ref. 6
the previous four approaches
Palladium catalysis plays an important role in organic
synthesis. A variety of fundamental transformations, such
as hydrogenation of multiple bonds,7 cross-coupling reac-
tions,8 heteroatoms (N, O, S) arylations,9 C–H bond
functionalizations10 and so on,11 rely heavily on palladium
species. Recently, much attention has been paid to the pal-
ladium-catalyzed cascade process for efficient synthesis
of heterocycles.12
this work
O
O
N
R1
O
NH2
O
OEt
Pd
heat
R1
+
R2
X
R2
1
3
2
O
O
OEt
Pd
R1
NH
The development of cascade process for efficient synthe-
sis of biologically active heterocycles via Pd-catalysis is
heat
amination
lactamization
R2
SYNLETT 2012, 23, 601–606
x
x
.
x
x
.
2
0
1
1
Advanced online publication: 10.02.2012
DOI: 10.1055/s-0031-1290346; Art ID: W69911ST
© Georg Thieme Verlag Stuttgart · New York
Scheme 1 Strategies for synthesis of 4H-benz[1,4]oxazin-3-ones

602
G. Feng et al.
LETTER
Ethyl 2-(2-iodophenoxy)acetate and aniline were used as groups also provided the products 1h–l in good yields. In
the model substrates to optimize the reaction conditions in addition, the reaction of 4-trifluoromethoxyaniline and 1-
terms of catalyst,13 ligand, base, temperature, and catalyst naphthylamine with ethyl 2-(2-iodophenoxy)acetate pro-
loading under N2 atmosphere. Ethyl 2-(2-iodophe- vided the corresponding products in 88% and 68% yields,
noxy)acetate was prepared in 95% yield by treating 2-io- respectively. On comparing the yield of 1b with 1c, or 1i
dophenol with ethyl 2-bromoacetate in the presence of with 1j, it is obvious that ortho-substituted anilines show
K2CO3 at room temperature for three hours.14,15 The re- some steric effect, resulting in ca. 10% lower yield than
sults are summarized in Table 1. We used toluene as the their para counterpart.
solvent as it is less toxic and commonly employed in Pd-
Subsequently, we investigated the reaction of ethyl 2-(2-
catalyzed N-arylation reactions. Also, the reaction tem-
bromophenoxy)acetate with aromatic amines under the
perature and time were set at 90 °C and 24 hours, respec-
same conditions. According to the data in Table 2, we can
tively. Initially, the combination of Pd(OAc)2 (10 mol%),
conclude that the yields obtained from the bromides were
much lower than those of the iodides (1b, 1d, and 1m), ex-
cept for one case that produced 4-phenyl-4H-benz[1,4]ox-
BINAP (10 mol%), and K2CO3 (2.0 equiv) was tried, but
no expected product was observed after heating the reac-
tion mixture at 90 °C for 24 hours (entry 1). When t-BuO-
azin-3-one (1a) in the comparable yield of 91%. These
Na was used as the base, the desired product was isolated
results indicate that bromides exhibited lower reactivity,
in 28% yield, along with 68% conversion of the starting
which was consistent with the reported reactivity order. It
ethyl 2-(2-iodophenoxy)acetate (entry 2). Gratifyingly,
is noteworthy that when the more challenging 2-(2-chlo-
the yield of 4-phenyl-4H-benz[1,4]oxazin-3-one (1a) was
rophenoxy)acetate was employed, 4-phenyl-4H-benz-
increased up to 96% and the starting ethyl 2-(2-iodophe-
noxy)acetate was consumed completely by employing
Cs2CO3 as the base (entry 3). The above results indicate
that the nature of base has great impact on the cascade pro-
cess. Therefore, Cs2CO3 was selected as the base in the
following optimizations. In an effort to find other efficient
phosphine ligand for the present transformation, dppf,
P(Ph)3, XPhos, and Xantphos were screened (entries 4–7)
and it was found that XPhos was as efficient as BINAP
(95% vs. 96%). Subsequently, the effect of palladium
source was investigated. It was found that Pd2(dba)3 was
not a good choice of catalyst for this process, as only 40%
yield and 77% conversion were observed (entry 8). On the
other hand, PdCl2 was found to be an effective precatalyst,
which provided the desired product in 92% yield (entry 9).
Finally, an effort for reducing the catalyst loading was at-
tempted. However, when the loading of catalyst and
ligand was reduced from 10 mol% to 5 mol%, the yield
and conversion were decreased to 50% and 51%, respec-
tively (entry 10). Meanwhile, we found that the yield
could be increased to 78% by simply raising the reaction
temperature to 110 °C (entry 11). Further enhancing the
reaction temperature to 120 °C afforded the product in
slightly higher yield (82% vs. 78%, entry 12).
Table 1 Optimization for the Synthesis of 4-Phenyl-4H-
benz[1,4]oxazin-3-onesa
O
O
NH2
O
N
O
OEt
Pd
+
I
1a
Entry Catalyst, ligand,c base
Temp
(°C)
Conv.
(%)d
Yield
(%)e
1
2
Pd(OAc)2, BINAP, K2CO3
Pd(OAc)2, BINAP, t-BuONa
Pd(OAc)2, BINAP, Cs2CO3
Pd(OAc)2, dppf, Cs2CO3
Pd(OAc)2, Ph3P, Cs2CO3
Pd(OAc)2, Xphos, Cs2CO3
Pd(OAc)2, Xantphos, Cs2CO3
Pd2(dba)3, BINAP, Cs2CO3
PdCl2, BINAP, Cs2CO3
90
–
68
100
48
–
0
90
28
96
46
trace
95
73
40
92
50
78
82
3
90
4
90
5
90
6
90
100
85
77
100
51
–
7
90
8
90
With the optimized conditions in hand, the generality of
the process was then investigated. Firstly, the reaction of
ethyl 2-(2-iodophenoxy)acetate with various anilines was
studied. As shown in Table 2, most of aryl amines exam-
ined provided the desired products in good to excellent
yields. Anilines possessing methyl group at ortho, meta,
or para positions provided the corresponding products in
excellent yields. In particular, the highly bulky 2,6-dime-
thylaniline also afforded the expected product in 61%
yield under the same conditions. Moreover, the reaction
was compatible with anilines bearing both electron-donat-
ing and electron-withdrawing groups. For example, para-
and meta-methoxyanlines exhibited high reactivity, fur-
nishing 1f and 1g in 80% and 72% yields, respectively.
9
90
10b
11b
12b
Pd(OAc)2, BINAP, Cs2CO3
Pd(OAc)2, BINAP, Cs2CO3
Pd(OAc)2, BINAP, Cs2CO3
90
110
120
90
a Reaction conditions: ethyl 2-(2-iodophenoxy)acetate (1.0 equiv),
catalyst (10 mol%), ligand (10 mol%), base (2.0 equiv), aniline (1.5
equiv), toluene (0.1 M), 90 °C, 24 h. All reactions were carried out in
a sealed vial.
b The loadings of Pd(OAc)2 and BINAP were 5 mol% and 5 mol%,
respectively. The reaction time was 24 h.
c Racemic BINAP was used.
d The conversion was calculated based on the recovered ethyl 2-(2-
iodophenoxy)acetate.
Meanwhile, anilines bearing Cl, Br, CF3, and COOEt e Isolated yield.
Synlett 2012, 23, 601–606
© Thieme Stuttgart · New York

LETTER
4H-Benz[1,4]oxazin-3-ones from Anilines and 2-(2-Halophenoxy)alkanoates
603
Table 2 Synthesis of 4-Aryl-4H-benz[1,4]oxazin-3-ones from 2-(2-
Halophenoxy)acetates and Aryl Amines via Pd-Catalyzed Cascade
Processa (continued)
[1,4]oxazin-3-one (1a) could be obtained in 45% yield
due to the incompletion of the reaction.
Table 2 Synthesis of 4-Aryl-4H-benz[1,4]oxazin-3-ones from 2-(2-
Halophenoxy)acetates and Aryl Amines via Pd-Catalyzed Cascade
Processa
O
O
Pd(OAc)2
BINAP
Cs2CO3
NH2
O
OEt
N
O
R
O
R
+
O
toluene
90 °C, 24 h
X
Pd(OAc)2
BINAP
NH2
O
OEt
Cs2CO3
N
O
R
X = I, Br, Cl
1a–n
R
+
toluene
90 °C, 24 h
X
Entry
Product
Yield
X = I, Br, Cl
1a–n
O
N
Entry
Product
Yield
O
7
X = I (72%)
O
N
X = I (96%)
X = Br (91%)
X = Cl (45%)
O
OMe
1
2
1g
O
N
1a
O
O
N
8
X = I (68%)
O
X = I (94%)
X = Br (63%)
Br
O
1h
1b
1c
1d
1e
N
O
O
N
9
X = I (75%)
X = I (63%)
X = I (85%)
O
O
O
O
3
4
5
X = I (84%)
Cl
O
1i
1j
O
N
N
O
10
Cl
X = I (93%)
X = Br (58%)
O
N
O
N
O
11
X = I (61%)
CF3
O
1k
O
N
N
O
6
X = I (80%)
12
X = I (79%)
OMe
COOEt
1f
1l
© Thieme Stuttgart · New York
Synlett 2012, 23, 601–606

604
G. Feng et al.
LETTER
Table 2 Synthesis of 4-Aryl-4H-benz[1,4]oxazin-3-ones from 2-(2-
Halophenoxy)acetates and Aryl Amines via Pd-Catalyzed Cascade
Processa (continued)
Table 3 Synthesis of 2-Alkyl-4-aryl-4H-benz[1,4]oxazin-3-ones
via Pd-Catalyzed Cascade Processa
O
N
R1
O
O
Pd(OAc)2
BINAP
Cs2CO3
O
NH2
O
Pd(OAc)2
BINAP
O
X
NH2
OEt
O
OEt
Cs2CO3
R2
N
O
R
R1
+
toluene
90 °C, 24 h
R
+
toluene
90 °C, 24 h
R2
X
X = I, Br
X = I, Br, Cl
1a–n
1o–t
Entry
Product
Yield
Entry
Product
Yield
O
N
O
N
O
O
O
O
X = I (90%)
X = Br (96%)
X = I (88%)
X = Br (75%)
1
13
OCF3
O
1o
1p
1m
1n
O
N
X = I (84%)
X = Br (83%)
2
3
N
O
14
X = I (68%)
O
N
a Reaction conditions: ethyl 2-(2-halophenoxy)acetate (1.0 equiv),
Pd(OAc)2 (10 mol%), ( )BINAP (10 mol%), Cs2CO3 (2.0 equiv),
amine (1.5 equiv), toluene (0.1 M), 90 °C, 24 h. All reactions were
carried out in a sealed vial.
X = Br (72%)
Finally, the influence of substitutions at the a position of
2-(2-halophenoxy)alkanoates was evaluated and the re-
sults are listed in Table 3. Gratifyingly, it was found that
alkyl groups (R1 = Et and Me) were beneficial for the pro-
cess, affording the products in excellent yields; even less
reactive 2-(2-bromophenoxy)alkanoates could be em-
ployed. Interestingly, with these alkyl groups in sub-
strates, the yields of 2-(2-bromophenoxy)alkanoates were
comparable with those of the corresponding aryl iodides.
1q
O
N
O
4
5
X = Br (96%)
1r
1s
In summary, we have established a novel cascade proto-
col,16 consisting of Pd-catalyzed intermolecular amination
and spontaneous cyclization, for efficient synthesis of 4H-
benz[1,4]oxazin-3-ones from readily available starting
materials. It was found that Cs2CO3 used as the base is
crucial for the transformation and alkyl groups at a-posi-
tion of ethyl 2-(2-halophenoxy)alkanoates is beneficial
for achieving high yields. The process developed shows
good generality, thus it is quite attractive for efficient syn-
thesis of a library of 4H-benz[1,4]oxazin-3-ones. It should
be useful in pharmaceutical and biochemical field.
O
N
O
X = Br (92%)
O
N
O
6
X = Br (90%)
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
OCF3
1t
a Reaction conditions: ethyl 2-(2-halophenoxy)acetate (1.0 equiv),
Pd(OAc)2 (10 mol%), ( )BINAP (10 mol%), Cs2CO3 (2.0 equiv),
amine (1.5 equiv), toluene (0.1 M), 90 °C, 24 h. All reactions were
carried out in a sealed vial.
Synlett 2012, 23, 601–606
© Thieme Stuttgart · New York

LETTER
4H-Benz[1,4]oxazin-3-ones from Anilines and 2-(2-Halophenoxy)alkanoates
605
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Song, Q.; Qi, C.; Zhang, X.-M. J. Org. Chem. 2011, 76,
9261.
Acknowledgment
Financial support by the University of Shaoxing is acknowledged
with thanks. We also thank Dr. Jinglong Wu at the Zhejiang Univer-
sity for helpful discussion.
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Z.; Buchwald, S. L. Org. Lett. 2012, 14, 170. (b) Ueda, S.;
Su, M.; Buchwald, S. L. J. Am. Chem. Soc. 2011, 133: DOI:
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(16) General Procedure for the Synthesis of 4H-
Benz[1,4]oxazin-3-ones: To a 10-mL pressurized process
vial were added magnetic stir bar, Pd(OAc)2 (6.8 mg, 0.03
mmol, 10 mol%), ( )-BINAP (18.7 mg, 0.03 mmol, 10
mol%), ethyl 2-(2-halophenoxy)alkanoates (0.30 mmol),
and Cs2CO3 (195 mg, 0.6 mmol). The loaded vial was then
sealed with a rubber cap. The vial was evacuated and
backfilled with nitrogen through the cap (this procedure was
repeated several times). The anhyd and degassed toluene (3
mL) and aryl amine (0.45 mmol) were added by syringe
through the cap. The resultant mixture was heated at 90 °C
for 24 h in an oil bath, and then filtrated through Celite with
washing with EtOAc. The combined filtrate was concen-
trated under reduced pressure. The residue was purified by
column chromatography on silica gel, eluting with EtOAc
and petroleum ether (60–90 °C) to afford 1.17,18 The
structures and yields of the products are given in Tables 2
and 3.
(17) Physical and spectroscopic data for 4-naphthanyl-4H-
benz[1,4]oxazin-3-one (1n): yellow crystalline solid; mp
146–147 °C; Rf 0.55 (EtOAc–hexane, 25%). IR (film): 1682,
1370 cm–1. 1H NMR (400 MHz, CDCl3): d = 7.95 (d, J = 8.0
Hz, 1 H), 7.91 (d, J = 8.0 Hz, 1 H), 7.55–7.61 (m, 2 H), 7.39–
7.49 (m, 3 H), 7.07 (d, J = 8.0 Hz, 1 H), 6.94 (dd, J = 8.4, 8.4
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1 H), 4.91, 4.84 (AB q, J = 15.6, 15.6 Hz, 2 H). 13C NMR
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130.1, 129.8, 128.8, 127.55, 127.52, 126.8, 126.0, 124.2,
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© Thieme Stuttgart · New York
Synlett 2012, 23, 601–606

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LETTER
122.9, 122.4, 117.1, 116.9, 68.3. MS (+ESI): m/z = 298 (53)
[M + Na+], 572 (100) [2 M + Na+]. Anal. Calcd for
C18H13NO2: C, 78.53; H, 4.76; N, 5.09. Found: C, 78.56; H,
4.79; N, 4.98.
2 H), 7.06 (dd, J = 8.0, 1.2 Hz, 1 H), 6.99 (ddd, J = 8.0, 8.0,
1.6 Hz, 1 H), 6.85 (ddd, J = 8.0, 8.0, 1.6 Hz, 1 H), 6.44 (dd,
J = 8.0, 1.2 Hz, 1 H), 4.66 (dd, J = 8.4, 4.4 Hz, 1 H), 2.44 (s,
3 H), 1.95–2.10 (m, 2 H), 1.16 (t, J = 7.6 Hz, 3 H). 13C NMR
(100 MHz, CDCl3): d = 166.3, 143.8, 138.7, 133.6, 130.8,
130.6 (2 ×), 128.5 (2 ×), 123.9, 122.2, 117.3, 116.6, 78.8,
23.9, 21.3, 9.6. MS (+ESI): m/z = 290 (28) [M + Na+], 557
(100) [2 M + Na+]. Anal. Calcd for C17H17NO2: C, 76.38; H,
6.41; N, 5.24. Found: C, 76.36; H, 6.39; N, 5.37.
(18) Physical and spectroscopic data for 2-ethyl-4-(4-methyl-
phenyl)-4H-benz[1,4]oxazin-3-one (1r): yellowish
crystalline solid; mp 95–96 °C; Rf 0.72 (EtOAc–hexane,
25%). IR (film): 1689, 1368 cm–1. 1H NMR (400 MHz,
CDCl3): d = 7.34 (d, J = 8.0 Hz, 2 H), 7.16 (d, J = 8.0 Hz,
Synlett 2012, 23, 601–606
© Thieme Stuttgart · New York

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Copyright of Synlett is the property of Georg Thieme Verlag Stuttgart and its content may not be copied or
emailed to multiple sites or posted to a listserv without the copyright holder's express written permission.
However, users may print, download, or email articles for individual use.