Efficient stereoselective synthesis of benzoxazines via copper-catalyzed three-component coupling reactions

Article abstract of DOI:10.1016/j.tetlet.2008.10.080

A convenient one-pot synthesis of 1,4-benzoxazines via three-component coupling and subsequent O-cyclization is reported. The present reaction provides an efficient protocol to functionalized 1,4-benzoxazine derivatives in good to high yields from aldehyd

Full text of DOI:10.1016/j.tetlet.2008.10.080

Tetrahedron Letters 50 (2009) 57–59
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Efficient stereoselective synthesis of benzoxazines via copper-catalyzed
three-component coupling reactions
*
Xiaobing Xu, Linfeng Liang, Jun Liu, Jingyu Yang, Lugen Mai, Yanzhong Li
Institute of medicinal chemistry, Shanghai Key Laboratory of Green Chemistry and Chemical Processes, Department of Chemistry, East China Normal University,
3663 North Zhongshan Road, Shanghai 200062, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
A convenient one-pot synthesis of 1,4-benzoxazines via three-component coupling and subsequent
O-cyclization is reported. The present reaction provides an efficient protocol to functionalized 1,4-benz-
oxazine derivatives in good to high yields from aldehydes, amines and alkynes. Furthermore, the O-annu-
lation process is completely regio- and stereoselective, only the six-membered rings and its Z-isomers
were obtained.
Received 7 August 2008
Revised 15 October 2008
Accepted 17 October 2008
Available online 22 October 2008
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
Copper catalyst
Benzoxazines
Three-component couplings
One-pot synthesis
Benzoxazines are important scaffolds of natural products and
therapeutic agents. Various benzoxazine derivatives have been
shown to be biologically active or have pharmacological properties.1
As a consequence, several methods for the synthesis of benzoxazine
derivatives have been reported.2 However, most of the methods re-
ported were multi-step procedures and lacked generality, and rather
complex workup and purification procedure have limited a wider
application. Thus, there is a need to develop a general and efficient
routeforitssynthesis. Ontheotherhand, multi-componentcoupling
reactions have attracted much attention in recent years.3 This strat-
egy allows quickaccessto structurally diversecompoundsfromsim-
ple starting materials in an environmentally benign fashion.
Especially, the three-component coupling of aldehydes, amines
and alkynes (A3 coupling) towards propargylamines mediated or
catalyzed by Cu,4 Ag,5 Au,6 Ru/Cu7 and Ir8 was disclosed. Other pro-
cedures assisted by ionic liquid,9 supported catalysts,10 micro-
wave11 and ultrasound12 were also reported. Inspired by these
developments, we have envisioned that if the arylamines bearing
ortho-oxygen nucleophile were employed in the A3 coupling reac-
tion, a sequential intramolecular nucleophilic attack of the oxygen
to the triple bond might occur to furnish the benzoxazine deriva-
tives. Herein, we report for the first time the one-pot preparation
of the benzoxazine derivatives through A3 coupling reactions cata-
lyzed by copper.
paraformaldehyde (2.0 equiv) and phenylacetylene (2a) (1.5 equiv)
with CuCl (2 mol %) as catalyst in dioxane at 110 °C. The reaction
afforded the corresponding propargylamine, 2-(methyl(3-phenyl-
prop-2-ynyl)amino)phenyl 4-methylbenzenesulfonate (4)2a in
only 20% yield after 18 h, and no cyclized product could be de-
tected (Table 1, entry 1). When the solvent was changed to DMF,
4 was produced in 43% yield (Table 1, entry 2).
Increasing the reaction temperature, the desired product could
be isolated in nearly quantitative yield after 8 h (Table 1, entry 3).
Without the addition of triethylamine, the yield was decreased
considerably (Table 1, entry 4). The role of Et3N may be the
Table 1
Screening of reaction conditions for A3 coupling reactions
H
N
Ph
2.0 eq (CH2O)n , 2% Cu salt
N
OTs
1a
1.5 eq Ph
, Et3N
OTs
4
Entry
Cu salt
Solvent
Triethylamine
(equiv)
Temperature
(°C)
Time
(h)
Yielda
(%)
1
2
3
4
5
6
7
8
CuCl
CuCl
CuCl
CuCl
None
CuBr
CuI
Dioxane
DMF
DMF
DMF
DMF
DMF
DMF
DMF
3.0
3.0
3.0
None
3.0
3.0
3.0
3.0
110
110
130
130
130
130
130
130
18
24
8
8
8
8
8
8
20
43
98
76
0
96
84
68
Initially, we examined the three-component coupling reaction
using 2-(methylamino)phenyl-4-methylbenzenesulfonate (1a),
CuCN
* Corresponding author. Tel./fax: +86 21 62233969.
E-mail address: yzli@chem.ecnu.edu.cn (Y. Li).
a
Isolated yield.
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.10.080

58
X. Xu et al. / Tetrahedron Letters 50 (2009) 57–59
Table 2
Screening of reaction conditions for the one-pot formation of benzoxazines
H
N
N
KOH, EtOH/H2O
80 oC, Time(2)
Et N
CuCl,
3
+
+
(CH2O)n
Ph
Time(1)
OTs
O
Ph
1a
3a
Entry
CuCl (mol %)
Solvent
Temperature (°C)
Time (1) (h)
KOH (equiv)
Time (2) (h)
Yielda (%)
b
1
2
3
4
5
6
7
8
9
2
10
10
10
20
20
20
20
20
20
DMF
130
110
110
110
110
110
110
110
130
130
8
20
20
20
20
20
20
20
20
18
10
5
10
19
5
10
19
10
10
10
10
12
12
12
12
12
12
9
—
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Ph2O
34
37
40
36
63
57
85c
68c
63c
9
9
10
DMSO
a
Isolated yield, the ratio of amine: phenylacetylene:paraformaldehyde is 1.0:1.5:2.0.
A complex mixture was obtained.
Phenylacetylene (2.0 equiv) and paraformaldehyde (3.0 equiv) were used.
b
c
Table 3
Preparation of 1,4-benzoxazine derivatives
Entry
Amine
Acetylene
Product
Yielda (%)
H
N
N
O
Ph
1
85
3a
3b
2a
OTs
Ph
1a
N
O
Cl
2
1a
1a
1a
71
2b
p
-ClC6H4
N
MeO
3
73
3c
O
2c
p
-MeOC6H4
4
5
6
30b
74b
66b
O
O
3d
N
N
2d
allyl
N
H
N
2a
2c
3e
Ph
O
OTs
1b
allyl
N
1b
3f
O
p-MeOC6H4

X. Xu et al. / Tetrahedron Letters 50 (2009) 57–59
59
Table 3 (continued)
Entry
Amine
Acetylene
Product
Yielda (%)
Bn
N
H
N
Ph
7
8
2a
63b
3g
Ph
OTs
O
1c
Bn
N
1c
2c
70b
3h
O
p-MeOC6H4
a
Isolated yields.
Reactions were carried out in DMSO at 130 °C.
b
neutralization of the in situ generated HCl. No reaction occurred in
the absence of a copper catalyst (Table 1, entry 5). Other copper(I)
salts were less effective as the yields decreased from CuBr to CuI
and CuCN (Table 1, entries 6–8). It was clear that the optimized
reaction condition for A3 coupling to propargylamine was to use
2 mol % of CuCl, 3.0 equiv of Et3N in DMF at 130 °C.
yields through copper-catalyzed three-component couplings. This
novel process constitutes a straightforward protocol to functional-
ized 1,4-benzoxazines from simple precursors. Further studies of
its scope and efficiency are currently under investigation in our
group.
In order to achieve the intramolecular O-cyclization, KOH was
then added to the reaction mixture since detosylation usually oc-
curred easily through alkaline hydrolysis. However, only trace of
the cyclized product could be detected after 10 h, and a complex
mixture was obtained (Table 2, entry 1). Various reaction conditions
were examined by changing the amount of catalyst, KOH, reaction
temperature and solvents (Table 2, entries 2–10). After a survey of
reaction conditions, it was observed that the reaction was best per-
formed using 20 mol % CuCl as the catalyst, dioxane as the solvent at
110 °C followed by the addition of EtOH/H2O and 10 equiv of KOH at
80 °C, and the desired 1,4-benzoxazine derivative (3a) was obtained
in 85% isolated yield (Table 2, entry 8). The O-annulation proceeded
in a completely regio- and stereoselective manner. In the 1H NMR
spectrum, the chemical shift of the vinylic hydrogen could be seen
at 5.34 ppm, this indicates a Z-stereochemistry of compound 3a.2a
And no seven-membered ring compound was isolated.
Having established an effective three-component coupling reac-
tions and the subsequent intramolecular O-cyclization system, we
then synthesized a variety of aminophenyl tosylate (1) to explore
the scope of the one-pot 1,4-benzoxazine forming reaction. The rep-
resentative results are shown in Table 3. When N-methyl substi-
tuted aminophenyl tosylate (1a) was used, it reacted with both
terminal alkynes bearing an electron-withdrawing group (p-ClC6H4)
and electron-donating substituent (p-MeOC6H4) to give the corre-
sponding 1,4-benzoxines in 71% and 73% yields, respectively (Table
3, entries 2 and 3). However, when N-allyl substituted aminophenyl
tosylate (1b) was employed under the same reaction conditions, the
yield of the desired product was rather low. Switching the solvent to
DMSO, the N-allyl substituted 1,4-benzoxazine (3e) was produced in
74% yield (Table 3, entry 5). N-Benzyl substituted aminophenyl tos-
ylate (1c) is also suitable for this reaction, it reacts with phenylacet-
ylene and p-methoxyphenylacetylene to give the corresponding 1,4-
benzoxazines 3g and 3h in 63% and 70% yields, respectively (Table 3,
entries 7 and 8). It was a Z-isomer as the chemical shift of the vinylic
hydrogen of 3h was at 5.34 ppm. To our delight, the crystal of 3h was
suitable for single crystal analysis, and its structure was fully charac-
terized by X-ray diffraction study which supported its structure and
the Z-stereochemisty. Interestingly, the treatment of 1a with 1,3-
diethynylbenzene (2d) in DMSO resulted in the bis(benzoxazinyl)
derivative 3d in 30% yield (Table 3, entry 4).
Acknowledgement
We are grateful to the National Natural Science Foundation of
China (20572025) for financial support.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2008.10.080.
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In summary, we have developed an efficient one-pot procedure
for the preparation of 1,4-benzoxazine derivatives in good to high