Unexpected TFA-catalyzed tandem reaction of benzo[d]oxazoles with 2-oxo-2-arylacetic acids: Synthesis of 3-aryl-2H-benzo[b][1,4]oxazin-2-ones and cephalandole A

Article abstract of DOI:10.1039/c4ra01605j

A convenient and efficient method for the TFA-catalyzed synthesis of 3-aryl-2H-benzo[b][1,4]oxazin-2-ones via a tandem reaction of benzo[d]oxazoles with 2-oxo-2-arylacetic acids was reported for the first time. The efficiency of this transformation was demonstrated by compatibility with a wide range of functional groups. The synthetic utility of this method was confirmed by the synthesis of the natural product cephalandole A. Moreover, a plausible mechanism for the formation of 3-aryl-2H-benzo[b][1,4]oxazin-2-ones involving ring-opening and cyclization steps is proposed. The present synthetic route to 3-aryl-2H-benzo[b][1,4]oxazin-2-ones could be readily scaled up to gram quantity without difficulty.

Full text of DOI:10.1039/c4ra01605j

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Unexpected TFA-catalyzed tandem reaction of
benzo[d]oxazoles with 2-oxo-2-arylacetic acids:
synthesis of 3-aryl-2H-benzo[b][1,4]oxazin-2-ones
and cephalandole A†
Cite this: RSC Adv., 2014, 4, 16705
Received 24th February 2014
Accepted 18th March 2014
a
b
a
Shaoxi Yan, Leping Ye, Miaochang Liu, Jiuxi Chen, a Jinchang Ding,a Wenxia Gao,a
*
DOI: 10.1039/c4ra01605j
a
a
*
Xiaobo Huang and Huayue Wu
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A convenient and efficient method for the TFA-catalyzed synthesis of condensation of O-methyl-o-quinonemonoximes with arylace-
3-aryl-2H-benzo[b][1,4]oxazin-2-ones via a tandem reaction of benzo- tates. In 2006, Yavari and co-workers12 reported that vinyl-
[d]oxazoles with 2-oxo-2-arylacetic acids was reported for the first phosphonium salt mediated reaction between o-aminophenols
time. The efficiency of this transformation was demonstrated by and alkyl propiolates leading to the synthesis of 3-alkyl-2H-
compatibility with a wide range of functional groups. The synthetic benzo[b][1,4]-oxazin-2-ones. In 2008, Kikelj and co-workers13
utility of this method was confirmed by the synthesis of the natural developed the synthesis of 4-benzyl- and 4-alkyl-3,4-dihydro-1,4-
product cephalandole A. Moreover, a plausible mechanism for the benzoxazin-2-one derivatives from ethyl 2-(2-hydroxy-
formation of 3-aryl-2H-benzo[b][1,4]oxazin-2-ones involving ring- phenylamino)acetate and aldehydes. Recently, Ballini and co-
opening and cyclization steps is proposed. The present synthetic workers14 reported the preparation of 1,4-benzoxazin-2-one
route to 3-aryl-2H-benzo[b][1,4]oxazin-2-ones could be readily derivatives via a domino reaction of o-aminophenols with ethyl
scaled up to gram quantity without difficulty.
b-nitroacrylates. As part of the continuing efforts in our labo-
ratory towards the development of new methods for the
synthesis of nitrogen-containing heterocycles,15 we herein
reported an unexpected TFA-catalyzed tandem reaction of
benzo[d]oxazoles with 2-oxo-2-arylacetic acids to access 2H-
benzo[b][1,4]oxazin-2-ones under mild conditions (Scheme 1).
Our preliminary studies focused on the model reaction
between 2-benzo[d]oxazole (1a) and 2-oxo-2-phenylacetic acid
(2a) to obtain 2-phenylbenzo[d]oxazole (4a) via cascade reaction
of decarboxylation, decarbonylation and coupling reaction
(Scheme 2). Through the screening process, little-to-no target
product 4a was detected using silver salts and palladium salts as
catalysts with a variety of parameters. To our surprise, a trace
amount of unexpected 3-phenyl-2H-benzo[b][1,4]oxazin-2-one
(3a) was observed by gas chromatography/mass spectrometry
(electron ionization) [GC/MS (EI)] analysis using triuoroacetic
acid (TFA) as the Brønsted acid in toluene (Table 1, entry 1). We
were delighted to nd that the yield of 3a could be improved to
45% under an air atmosphere aer solvent was changed
to acetonitrile (Table 1, entry 2). This nding inspired us to
1,4-Benzoxazines,1 as an important class of heterocycles, have
become increasingly important because they have been associ-
ated with a wide range of pharmacological and biological
activities.2 Among them, 2H-benzo[b][1,4]oxazin-2-one scaffolds
have been studied intensively in the past few years because they
are synthetic building blocks,3 present in a wide variety of
bioactive molecules, as well as photoactive molecules4 which
possess uorescent,5 photophysical and photochemical prop-
erties.6 In 2006, the 2H-benzo[b][1,4]oxazin-2-one-based natural
product cephalandole A was originally isolated from the
Taiwanese orchid Cephalanceropsis gracilis (Orchidaceae),7
which had previously been misassigned, and later corrected by
Bergman8 and Gross9 (Fig. 1).
The importance of 2H-benzo[b][1,4]oxazin-2-ones has resul-
ted in the development of different synthetic strategies for their
preparation. In general, 2H-benzo[b][1,4]oxazin-2-ones are
synthesized by the treatment of o-aminophenols with
a-ketoesters.10 Nicolaides and co-workers11 reported 3-aryl-2H-
benzo[b][1,4]oxazin-2-ones could be obtained by the
aCollege of Chemistry & Materials Engineering, Wenzhou University, Wenzhou 325035,
P. R. China. E-mail: jiuxichen@wzu.edu.cn; huayuewu@wzu.edu.cn
bThe Second Affiliated Hospital, Wenzhou Medical University, Wenzhou 325000, P. R.
China
† Electronic supplementary information (ESI) available: Analytical data and
spectra (1H, 13C NMR) for all products. See DOI: 10.1039/c4ra01605j
Fig. 1 The revised structure of cephalandole A.
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found that isopropanol was superior to DMSO, DMF, 1,2-
dichloroethane, dioxane, CH3CN, toluene, THF, and EtOH
(Table 1, entries 1–9). We also studied inuence of the amount
of TFA on the reaction yields. The results showed that 0.2
equivalents of TFA was sufficient, and excessive amount of
catalyst did not increase the yield (Table 1, entries 9–13). Then
various Brønsted acids were screened to examine their effect on
the reaction. Replacement of TFA with other acids, including
AcOH, PhCO2H, p-NO2PhCO2H, CF3SO3H, p-MePhSO3H, and
p-NO2PhSO3H, resulted in lower yields (Table 1, entries 14–19).
The yield was decreased to some extent when the reaction was
carried out at the lowered or elevated temperature (Table 1,
entries 20 and 21). Therefore, the optimal reaction condition
was to use 0.2 equiv. of TFA in isopropanol at 70 ꢀC under air. As
a result, the model reaction was carried out under optimized
conditions with 0.2 equiv. of TFA in isopropanol at 70 ꢀC under
air, which led to 3a in 94% yield (Table 1, entry 12).
Scheme 1 Synthesis of 2H-benzo[b][1,4]oxazin-2-ones.
With the optimized reaction conditions in hand, we next
explored the scope and generality of the reaction using various
2-benzo[d]oxazoles with 2-oxo-2-arylacetic acids (Table 2). First,
the reaction between benzo[d]oxazole (1a) and various 2-oxo-2-
arylacetic acids (2a–2k) was investigated under the standard
reaction conditions. The electronic properties of the substitu-
ents on the phenyl ring of the 2-oxo-2-arylacetic acids had an
obvious impact on the yield of the reaction. The 2-oxo-2-aryl-
acetic acids bearing an electron-withdrawing substituent (e.g.,
–F, –Cl, –Br, –I, –CN, and –NO2) produced higher yields of
products than those analogues bearing an electron-donating
substituent (e.g., –Me, and –OMe) (Table 2, entries 2–9).
Substrate 2-(naphthalen-2-yl)-2-oxoacetic acid (2j) reacted with
1a to give the desired product 3j in 88% yield (Table 2, entry 10),
but a lower yield was observed when substrate 2-(furan-2-yl)-2-
oxoacetic acid (2k) bearing a heteroaryl group was used as a
substrate (Table 2, entry 11).
We next explored the effect of the reaction of 2-oxo-2-phe-
nylacetic acids (2a) with various benzo[d]oxazoles (1b–1j) under
the standard reaction conditions, and the results are summa-
rized in Table 3. As expected, the groups on the phenyl ring of
benzo[d]oxazoles, such as methyl, methoxy, tert-butyl, chloro,
nitro, ester, and triuoromethyl, were quite compatible under
the optimized reaction conditions. The electronic properties of
the groups on the phenyl ring moiety of benzo[d]oxazoles had
some effects on the reaction. Generally, benzo[d]oxazoles pos-
sessing either electron-donating or electron-withdrawing groups
on the phenyl ring provided the corresponding 3-aryl-2H-benzo-
[b][1,4]oxazin-2-ones in good yields. However, substrate con-
taining a strong electron-withdrawing substituent (e.g., –NO2) on
the benzene ring, such as 5-nitrobenzo[d]oxazole (1f), achieved
the corresponding desired products 6-nitro-3-phenyl-2H-benzo-
[b][1,4]oxazin-2-one (3p) in moderate yield (59%, Table 3, run 5).
It would be specially mentioned that 5-arylbenzo[d]oxazoles (1h–
1j) are also good substrates for this transformation, and the
corresponding desired product 3r–3t were isolated in 87%, 93%,
Scheme
acetic acid.
2 Reaction of 2-benzo[d]oxazole with 2-oxo-2-phenyl-
Table 1 Screening for optimal reaction conditionsa
Entry
Catalyst
Equiv. (x)
Solvent
Yield b(%)
1
2
3
4
5
6
7
8
TFA
TFA
TFA
TFA
TFA
TFA
TFA
TFA
TFA
TFA
TFA
TFA
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
0.5
0.3
0.2
0.1
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
Toluene
CH3CN
DMSO
DMF
Dichloroethane
Dioxane
THF
Trace
45
11
Trace
14
88
82
84
91
93
94
94
81
59
66
45
39
54
EtOH
9
iPrOH
iPrOH
iPrOH
iPrOH
iPrOH
iPrOH
iPrOH
iPrOH
iPrOH
iPrOH
iPrOH
iPrOH
iPrOH
10
11
12
13
14
15
16
17
18
19
20
21
TFA
AcOH
PhCO2H
p-NO2PhCO2H
CF3SO3H
p-MePhSO3H
p-NO2PhSO3H
TFA
68
82c
89d
TFA
a
Reaction conditions: 1a (0.2 mmol), 2a (0.3 mmol), TFA (x mmol),
iPrOH (2 mL), air, 70 ꢀC, 18 h. Isolated yield. c At 60 ꢀC. d At 80 ꢀC.
b
examine optimal reaction conditions for the synthesis of 3a in 91% yield, respectively (Table 3, runs 7–9).
order to obtain more satisfactory results.
Treatment of 2-oxo-2-alkylacetic acid such as 2-oxo-2-
Considering solvents always played important roles in methylacetic acid (2l) with 1a under the optimized conditions
organic reactions, we rst examined the solvent effect and afforded the desired product 3u in 36% yield (Scheme 3).
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Table 2 Reaction of benzo[d]oxazole with 2-oxo-2-arylacetic acida
Table 3 Reaction of different benzo[d]oxazoles with 2-oxo-2-phe-
nylacetic acida
Entry
1
Ar (2)
Product (3)
Yield b(%)
94
Ph (2a)
2
3
4
5
6
p-MeC6H4 (2b)
p-OMeC6H4 (2c)
p-FC6H4 (2d)
p-ClC6H4 (2e)
p-BrC6H4 (2f)
83
45
93
95
91
a
Reaction conditions: 1 (0.2 mmol), 2a (0.3 mmol), TFA (0.04 mmol),
iPrOH (2 mL), air, 70 ꢀC, 18 h. Isolated yield was given in parenthesis.
7
p-IC6H4 (2g)
89
Scheme 3 Reaction of benzo[d]oxazole with 2-oxo-2-methylacetic
acid.
8
p-CNC6H4 (2h)
p-NO2C6H4 (2i)
2-naphthyl (2j)
90
85
88
9
Scheme 4 Applications in the synthesis of the natural product.
10
11
2-furyl (2k)
32
a
Reaction conditions: 1 (0.2 mmol), 2a (0.3 mmol), TFA (0.04 mmol),
iPrOH (2 mL), air, 70 ꢀC, 18 h. Isolated yield.
b
To demonstrate the synthetic utility of this method, it was
applied to the synthesis of the natural product cephalandole A
(Scheme 4). TFA-catalyzed tandem reaction of benzo[d]oxazoles
(1a) with 2-(1H-indol-3-yl)-2-oxoacetic acid (2m) afforded the
Scheme 5 Control experiments.
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Scheme 6 Gram-scale synthesis of 3a.
desired natural product cephalandole A in 86% yield through
single-step operation under the standard reaction conditions.
To elucidate the mechanism, some control experiments were
carried out under the standard reaction conditions as shown in
Scheme 5. If only benzo[d]oxazole (1a) was applied under the
standard reaction conditions, o-aminophenol (4) was isolated in
67% yield (Scheme 5a). However, no reaction happened and
almost 90% of reactant 2a was recovered when only 2-oxo-2-
phenylacetic acid (2a) was applied under the standard reaction
conditions (Scheme 5b). Under the standard reaction condi-
tions, when o-aminophenol reacted with 2a, afforded the
desired product 3a in 89% yield (Scheme 5c), suggesting that
o-aminophenol is a key intermediate. This result revealed that a
ring-opening pathway was taken in the reaction.
On the basis of the above experimental results, we proposed
a possible reaction pathway for the formation of 3-aryl-2H-
benzo[b][1,4]oxazin-2-ones. The rst step may involve the ring-
opening of benzo[d]oxazoles leading to o-aminophenol. Then
cyclization reaction of o-aminophenol with 2-oxo-2-arylacetic
acid in the presence of TFA delivers the corresponding 3-aryl-
2H-benzo[b][1,4]oxazin-2-ones as the products.
Finally, it is noteworthy that the present synthetic route to
3-aryl-2H-benzo[b][1,4]oxazin-2-ones could be readily scaled up
to gram quantity without difficulty. For instance, the reaction at
the 20 mmol scale afforded the corresponding product 3-phenyl-
2H-benzo[b][1,4]oxazin-2-one (3a) in 87% yield (Scheme 6).
In summary, we have developed a new strategy for con-
structing 3-aryl-2H-benzo[b][1,4]oxazin-2-ones from TFA-cata-
lyzed tandem reaction of benzo[d]oxazoles with 2-oxo-2-
arylacetic acids. In addition, the method provides an efficient
access to the natural product cephalandole A. Further efforts to
extend this catalytic system to the preparation of other useful
nitrogen-containing heterocycles are currently underway in our
laboratories.
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