Iodine Promoted One-Pot Synthesis of 2-Aryl Benzoxazoles from Amidoximes via Oxidative Cyclization and Ring Contraction

Article abstract of DOI:10.1002/ejoc.201901468

A molecular I₂-promoted one-pot synthesis of 2-aryl benzoxazoles has been developed by using amidoximes rather than the limited 2-aminophenols or 2-haloamides as substrates. The amidoxime substrates provided unique and efficient strategies for converting readily available aniline and benzaldehyde precursors into valuable chemicals. This transformation proceeded smoothly under transition-metal-free conditions through a sequential oxidative cyclization and ring contraction, and provided a potential route for introducing certain groups at any site of the scaffold.

Full text of DOI:10.1002/ejoc.201901468

A Journal of
Accepted Article
Title: Iodine Promoted One-pot Synthesis of 2-Aryl Benzoxazoles from
Amidoximes via Oxidative Cyclization and Ring Contraction
Authors: Yong Zhang and Min Ji
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201901468
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Supported by

10.1002/ejoc.201901468
European Journal of Organic Chemistry
COMMUNICATION
Iodine Promoted One-pot Synthesis of 2-Aryl Benzoxazoles from
Amidoximes via Oxidative Cyclization and Ring Contraction
Yong Zhang and Min Ji*[a]
Abstract: A molecular I2-promoted one-pot synthesis of 2-aryl
benzoxazoles has been developed by using amidoximes rather than
the limited 2-aminophenols or 2-haloamides as substrates. The
amidoxime substrates provided unique and efficient strategies for
converting readily available aniline and benzaldehyde precursors
into valuable chemicals. This transformation proceeded smoothly
under transition-metal-free conditions through a sequential oxidative
cyclization and ring contraction, and provided a potential route for
introducing certain groups at any site of the scaffold.
hexane).[11] To overcome these drawbacks, several transition-
metal catalyzed methods have been developed. The main
strategies are as follows: transition-metal catalyzed C-O cross-
coupling of 2-haloamides (path c in Scheme 1A)[12] and direct C-
H bond arylation of benzoxazoles (path d in Scheme 1A).[13]
Introduction
2-Aryl benzoxazoles are one type of heterocyclic compounds,
which are not only found in numerous natural products, but also
served as pharmacophores or important targets in drug
discovery. For examples, the 2-aryl benzoxazole scaffold is
found in naturally occurring cytotoxic compounds such as UK-1
and AJI9561.[1] Some of the medicinal chemistry applications of
2-aryl benzoxazoles include selective peroxisome proliferator-
antagonist JTP-426467,[2] estrogen
Figure 1. Examples of some biologically active 2-aryl benzoxazoles.
activated receptor
γ
receptor-β agonist ERB-041 and WAY-200070,[3] non-steroidal
anti-inflammatory drug Flunoxaprofen,[4] and the selective
transthyretin kinetic stabilizer Tafamidis (Figure 1).[5]
Furthermore, the unique chromophoric property renders them as
a scaffold in fluorescent probes.[6] 2-Aryl benzoxazoles also
serve as potential ligands in transition-metal catalyzed coupling
reactions.[7] Thus the development of effective methods for the
synthesis of 2-aryl benzoxazoles is synthetically fascinating.
The classical method for the synthesis of 2-aryl
benzoxazoles involves the condensation of 2-aminophenols with
various carbonyl compounds such as aldehydes or carboxylic
acid derivatives (path a in Scheme 1A). However, this method
suffered from harsh conditions (strong acid or high
temperature),[8] limited substrate scope (2-aminophenols), or
using oxidants to promote the cyclization of imine
intermediates.[9] In the 1950s, an intramolecular addition reaction
of the benzyne intermediates by side chain nucleophiles have
been developed to obtain 2-aryl benzoxazoles (path b in
Scheme 1A).[10] Although this protocol has been demonstrated in
previous works, it is recognized that this procedure is especially
problematic for large-scale operations with some disadvantages:
rather low reaction temperatures and the use of excess strong
base (generally potassium amide in liquid ammonia or n-BuLi in
Scheme 1. Synthesis of 2-aryl benzoxazoles.
Even though transition-metal catalysts have demonstrated
their power in synthesis, we believe that if they can be replaced
by metal-free analogues, the non-metal-catalyzed reactions will
have certain advantage in synthesis. In recent years,
hypervalent iodine catalyzed oxidative transformations have
emerged as complement strategies for C-O and C-N bonds
formation.[14] In 2017, Francke and coworkers reported a mild
method for the synthesis of benzoxazoles by using
[a]
Y. Zhang and Prof. M. Ji
School of Biological Science and Medical Engineering
Southeast University
Dingjiaqiao 87, 210009, Nanjing, China
E-mail: jiminseu@163.com
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
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10.1002/ejoc.201901468
European Journal of Organic Chemistry
COMMUNICATION
electrochemically generated hypervalent iodine.[9b] In the same
year, Shi and co-workers developed a base-free selective O-
arylation of amidoximes by diaryliodonium salts to have rapid
access to O-arylamidoximes and synthesize 2-substituted
and 2j). Amidoximes with meta-substituted R1 group afforded
two isomers with similar isolated yields under the standard
reaction conditions (e.g. 2m-1/2m-2, 2n-1/2n-2 and 2o-1/2o-2).
benzoxazole scaffolds through
a
sequence of [3,3]-
Table 1. Optimization of the reaction conditions[a]
.
rearrangements (Scheme 1B).[15] However, the method in
Scheme 1B proceeded through a two-step process and the
substituted diaryliodonium salt catalysts could not be obtained
from the commercial sources. Herein, we firstly report a one-pot
and transition-metal-free method for the synthesis of 2-aryl
benzoxazoles from amidoximes, which were easily prepared by
aniline and benzaldehyde precursors (Scheme 1C). The iodine,
a cheap, nontoxic and abundant halogen, functioned as the
catalyst.[16] The protocol also affords a potential route for
introducing certain groups at any site of the scaffold.
Additive
(equiv.)
I2
T
Time
[h]
Yield
[%][b]
Entry
Solvent
[equiv.]
[oC]
1
—
DMF
DMF
DMF
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
2.0
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.0
2.0
4.0
—
100
100
100
100
120
120
150
120
120
120
120
120
120
120
2
2
2
2
2
1
1
5
1
1
2
5
2
2
12
2
TFA
trace
42
48
56
56
55
43
46
49
39
0
3
AcOK (4.0)
AcOK (4.0)
AcOK (4.0)
AcOK (4.0)
AcOK (4.0)
AcOK (4.0)
AcOK (4.0)
AcOK (4.0)
AcOK (4.0)
AcOK (4.0)
AcOK (2.0)
AcOK (10.0)
Results and Discussion
4
The reaction is demonstrated by using (Z)-N-(4-chlorophenyl)-
N'-hydroxybenzimidamide (1a) in the presence of molecular
iodine (2.0 equiv.) under N2 atmosphere in DMF at 100 C for 2
5
o
6
h (Table 1, entry 1). The desired product 2a was obtained in
12% yield and unambiguously confirmed by X-ray
crystallography analysis (see Figure S1 in Supporting
Information).[17] The use of trifluoroacetic acid (TFA) as an
additive gave the target molecule with trace amount, whereas
AcOK (4.0 equiv.) led to a higher yield as 42% (entries 2 and 3).
A brief survey of solvents showed that N-methylpyrrolidone
(NMP) afforded superior results (see entry 4 and Supporting
Information for details). We next studied the effect of
temperature and time on reaction (Table 1, entries 5-8), a higher
7
8
9
10
11
12
13
14
o
yield as 56% was obtained at optimized temperature of 120 C
for 1h (entry 6). Subsequently, other base were examined, and
AcOK provided better results (see the Supporting Information for
1.5
1.5
45
56
o
details). We then screened the using amount of iodine at 120 C
[a] Reaction conditions: 1a (1 mmol) and solvent (4 mL) under N2 atmosphere.
[b] Isolated yield.
(Table 1, entries 9 and 10), and the optimized amount is 1.5
equivalents. Further increasing in the amount of I2 led to the
reduction of yield (Table 1, entry 11), and no reaction was
occurred in the absence of I2 (Table 1, entry 12), indicating the
essentiality of I2. In addition, reducing the amount of AcOK to 2.0
equivalents afforded product 2a in lower yield while 10.0
equivalents resulted in a same yield as 56% (Table 1, entries
13-14).
The substrates with R2 substituents on the aldoxime moiety
readily afforded corresponding benzoxazoles in 33-50% yields
(2s-2x). The reaction of the para-nitro amidoxime, 1z, gave
complex reaction mixtures and trace amount of 2z. This is
The generality and scope of the reaction are investigated in
Scheme 2, in which all substrates 1 with electron-donating or
electron-withdrawing groups on the phenyl ring are involved in
the reaction to afford the corresponding products (2b-2x). The
nature of the substituent R1 directly linked to the aniline moiety
was important to the reaction outcome. The substrates with
electron-withdrawing substituents (1d, 1e, 1h, 1i, 1j, 1l, 1m, 1n,
1o and 1p, except 1c) readily afforded the corresponding
products in 56-70% yields, whereas substrates with electron-
donating or rich aromatic substituents (1f, 1g, 1k, 1q, 1r) were
less reactive, giving the benzoxazoles in 26-48% yields.
Changing positons of R1 group on the phenyl ring significantly
affected the yield of reaction. For example, the yields increased
when the R1 group was at the ortho position (2a, 2h, 2d, 2i, 2e
probably because the nitroso intermediate with
a nitro
substituent (see Scheme 5) was too reactive, leading to the
overproduction of by-products.[18] To our disappointment, the
efforts to introduce methyl or isopropyl substituent at the C2
position of the benzoxazoles were failed, which may due to the
instability of the substrates in the reaction conditions. Although
our products were in moderate yields, it is noteworthy that
certain groups could be successfully introduced at any site of the
scaffold (e.g. 2d, 2i, 2n, 2t, 2w and 2x), especially at the remote
C7 position of benzoxazoles (products, such as 2l, 2m-2, 2n-2,
2o-2 and 2p-2, were rarely or never synthesized by other
methods).
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10.1002/ejoc.201901468
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COMMUNICATION
employed in the reaction without I2, the expected product 2b was
not observed (Scheme 4A). These results suggested that an
iodo intermediate
transformation.
A was not involved in the present
Scheme 2. Substrate scope for synthesis of 2-aryl benzoxazoles. [a] Reaction
was performed with 1 (1.0 mmol), AcOK (4.0 mmol) and I2 (1.5 mmol) in NMP
(4 mL) at 120 oC for 1-2 h; Yield of the isolated product shown. [b] Reaction
performed at 80 °C for 3 h.
Scheme 4. Survey of reaction pathway.
Scheme 3. Gram-scale synthesis of Tafamidis precursor 2y.
To further examine the effectiveness of this transformation, the
reaction was carried out on a gram scale with 5 mmol of 1y as
the substrate (Scheme 3). As expected, the reaction readily
afforded the desired 2-aryl benzoxazole 2y in 46% yield. It
should be noted that simple ester hydrolysis of 2y leads to the
formation of the FDA-approved drug Tafamidis.[5]
When 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO), a free
radical scavenger, was added under the standard reaction
conditions (entry 11, Table 1), the yield of target product 2a was
not affected (Scheme 4A). Therefore, the radical was not involve
in the present transformation. The initial mechanistic proposal
for the formation of 2a was shown in Scheme 4B. 1a reacted
with iodine to afford the iodo intermediate A, followed by a SNAr
process to give 1,2,4-benzoxadiazine B. Then, intermediate B
underwent a ring contraction to give the final product 2a.[19]
However, when 2-halo-substituted amidoximes (1h-1j) were
Scheme 5. A plausible mechanism.
A plausible mechanism of the formation of 2-aryl benzoxazoles
is proposed by using 1b as model (Scheme 5). Initially, 1b
reacted with I2 to afford an organic hypohalite C,[20] which was
subsequently oxidized to the corresponding nitroso intermediate
D under basic conditions.[20-21] Then intermediate D underwent
intramolecular cyclization to afford the intermediate E,[22] which
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10.1002/ejoc.201901468
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COMMUNICATION
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.
Conclusions
In summary,
a molecular I2-promoted transition-metal-free
protocol has been developed to construct 2-aryl benzoxazole
skeleton with reasonable yields from amidoximes. The
amidoxime substrates provided unique and efficient strategies
for converting readily available aniline and benzaldehyde
precursors into valuable chemicals. In addition, a series of 2-aryl
benzoxazoles with substituents at any positions of the ring were
obtained. A preliminary survey of reaction pathway disclosed
that this reaction might occur though a sequential oxidative
cyclization and ring contraction. Further studies to elucidate a
detailed mechanism for this protocol are currently underway in
our laboratory.
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Experimental Section
Genaral Procedure: To a mixture of amidoximes 1 (1.0 mmol), iodine
(1.5 equiv.) and AcOK (4.0 equiv.) was added 1-methyl-2-pyrrolidinone
(NMP, 4.0 mL) under nitrogen atmosphere at room temperature. The
reaction temperature was raised to 120 oC for 1-2 h. When TLC shows
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quenched with saturated Na2S2O3 aquesous (50 mL) and extracted with
EtOAc (3×20 mL). The extract was washed with brine and dried over
Na2SO4. The solvent was evaporated in vacuo and the residue was
purified by column chromatography on silica gel with ethyl
acetate/petroleum ether as an eluent to give the desired product 2.
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Acknowledgments
This work was supported by the National Natural Science
Foundation of China (81671745).
Keywords: Amidoximes • 2-Aryl benzoxazoles • Iodine
promoted • Oxidative cyclization • Ring contraction
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COMMUNICATION
An I2-promoted sequential oxidative
cyclization and ring contraction
reaction is developed for the synthesis
of 2-aryl benzoxazoles by using
amidoximes rather than the limited 2-
aminophenols or 2-haloamides as
substrates. This method provides a
potential route for introducing certain
groups at any site of the 2-aryl
benzoxazole scaffold.
Key Topic*
Yong Zhang, Min Ji*
Page No. – Page No.
Iodine Promoted One-pot Synthesis
of 2-Aryl Benzoxazoles from
Amidoximes via Oxidative Cyclization
and Ring Contraction
* Oxidative cyclization/ Ring contraction
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