Base-Free Selective O-Arylation and Sequential [3,3]-Rearrangement of Amidoximes with Diaryliodonium Salts: Synthesis of 2-Substituted Benzoxazoles

Article abstract of DOI:10.1002/adsc.201700906

A variety of functionalized 2-substituted benzoxazoles can be prepared in good yields from amidoximes and diaryliodonium salts by selective O-arylation and sequential [3,3]-rearrangement under metal-free conditions. O-arylation of amidoximes was promoted by 3 ? molecule sieves in the absence of a base and a sequential TFA-mediated [3,3]-rearrangement was used to synthesize 2-substituted benzoxazoles. Both of the O-aryl products and rearrangement products were compatible with a broad range of sensitive functional groups such as ester, aldehyde, nitro, vinyl, amine, and amide groups in addition to halides. A bidentate N-ligand with double benzoxazoles was prepared at gram-scale in two steps. (Figure presented.).

Full text of DOI:10.1002/adsc.201700906

Title: Base-Free Selective O-Arylation and Sequential [3,3]-
Rearrangement of Amidoximes with Diaryliodonium Salts:
Synthesis of 2-Substituted Benzoxazoles
Authors: Wei-Min Shi, Xiao-Hua Li, Cui Liang, and Dong-Liang Mo
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201700906
Link to VoR: http://dx.doi.org/10.1002/adsc.201700906

10.1002/adsc.201700906
Advanced Synthesis & Catalysis
COMMUNICATION
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Base-Free Selective O-Arylation and Sequential [3,3]-
Rearrangement of Amidoximes with Diaryliodonium Salts:
Synthesis of 2-Substituted Benzoxazoles
Wei-Min Shi,† Xiao-Hua Li,† Cui Liang, and Dong-Liang Mo*
a
State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources, Ministry of Science and
Technology of China; School of Chemistry and Pharmaceutical Sciences, Guangxi Normal University, 15 Yu Cai Road,
Guilin, 541004, China. E-mail: moeastlight@mailbox.gxnu.edu.cn
† W. M. Shi and X. H. Li contributed equally to this work
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
aminolphenols with various carbonyl compounds
Abstract.
A variety of functionalized 2-substituted
benzoxazoles can be prepared in good yields from such as carboxylic acids, aldehydes or acetyl
amidoximes and diaryliodonium salts by selective O-
chlorides followed by oxidative cyclization,[7] or
arylation and sequential [3,3]-rearrangement under metal-
free conditions. O-arylation of amidoximes was promoted
by 3Å molecule sieves in the absence of a base and a
sequential TFA-mediated [3,3]-rearrangement was used to
synthesize 2-substituted benzoxazoles. Both of the O-aryl
products and rearrangement products were compatible with
a broad range of sensitive functional groups such as ester,
aldehyde, nitro, vinyl, amine, and amide groups in addition
to halides. A bidentate N-ligand with double benzoxazoles
was prepared at gram-scale in two steps.
intramolecular cross-coupling of N-arylbenzamides
followed by C−O bond formation under transition
metal catalysts.[8] Although sophisticated examples
have been demonstrated in previous works, they
sometimes suffered from harsh conditions (strong
base or high temperature), limited substrate scope
(such as 2-aminophenols or its derivatives), toxic
transition metal catalysts, and functional group
tolerance. To overcome these drawbacks, an
alternative efficient and practical route to access
functionalized benzoxazoles is desirable.
Keywords: Amidoxime; Benzoxazoles; Diaryliodonium
salts; O-Arylation; [3,3]-Rearrangement
Cl
O
NH
F
O
O
OH
N
NO2
Me
N
HO
2-Substituted benzoxazoles are an important class
of common heterocyclic compounds,[1] which are not
only found in numerous natural products, but also
served as pharmacophores or important targets in
drug discovery.[2] Certain 2-substituted benzoxazoles
have been successfully applied in pharmaceuticals,
such as estrogen receptor-β agonist ERB-041,
selective peroxisome proliferator-activated receptor γ
antagonist JTP-426467, anticancer NSC-693638,
orexin-1 receptor antagonist SB-334867, herbicide
Fenoxaprop, and orexin antagonist MK-4305 (Figure
1).[3] Many methods have been reported to prepare 2-
substituted benzoxazoles from diverse starting
materials in the past decades involving transition-
metal catalysis or transition-metal-free strategies.[4,5]
ERB-041
JTP 426467
N
N
O
H
H
H
N
N
O
N
N
Me
N
N
N
O
Me
SB-334867
NSC 693638
N
N
O
N
O
O
O
OH
Me
O
N
N
Cl
N
N
Cl
Me
O
Me
Fenoxaprop
MK-4305
Figure 1. Examples of biologically active 2-substituted
benzoxazoles.
Common preparation methods always involve
a
cascade of C−H activation and crossing-coupling of
unsubstituted benzoxazole with halides or
organoboronic acids under Pd, Cu, Co, or Fe-
catalysts (Scheme 1-A),[6] or condensation of 2-
In recent years, diaryliodonium salts have served
as useful arylation reagents for C−O and C−N bonds
formation.[9] O-arylation and sequential [3,3]-
1
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10.1002/adsc.201700906
Advanced Synthesis & Catalysis
rearrangement to construct heterocyclic compounds
has become a powerful tool in organic synthesis; in
particular, O-arylation of N−O bond and subsequent
[3,3]-rearrangement is a strategy used to prepare
benzofurans.[10] In 2014, Kürti and co-workers
developed a base-mediated O-arylation of oximes by
diaryliodonium salts to have rapid access to O-
arylhydroxylamines and synthesize benzofuran
scaffolds through a sequence of [3,3]-rearrangements
(Scheme 1-B).[11] In the same year, Olofsson and co-
workers independently reported an efficient metal-
free one-pot synthesis of benzofurans in good yields
from ethyl acetohydroximate with diaryliodonium
salts (Scheme 1-C).[12] Although metal-free O-
arylation of N−O bonds that precede [3,3]-
rearrangement has been studied, the substrates are
limited, having only one nucleophilic site in the
molecule, and a strong base is required for the O-
arylation process. Currently, selective arylation for
substrates containing multiple nucleophilic sites
under metal-free conditions is still challenging owing
to the difficulty of controlling selectivity.[13] During
studies of selective arylation of N−O bonds in our
group,[14] to avoid using ortho-aminophenols as
starting materials, we postulated that selective O-
arylation of amidoximes containing two nucleophilic
sites followed by [3,3]-rearrangement on the N-atom
would directly afford 2-substituted benzoxazoles
(Scheme 1-D). Herein, we report a general strategy to
To test the possibility of selective O-arylation,
benzamidoxime 1a and diphenyliodonium triflate 2a
were chosen as model substrates for the initial O-
arylation studies for the synthesis of O-arylated
product 3aa using the conditions previously
described from our laboratory. Treatment of 1a and
2a with t-BuOK in DCE at 80 °C for 22 h afforded
the O-arylation product 3aa in 61% yield (Table 1,
entry 1). Solvent screening resulted in DCE giving
the best yield while a lower yield of product 3aa was
observed in toluene, MeCN, MeOH, THF, dioxane,
DMF, and DMSO (Table 1, entries 2-8). The type of
bases slightly affected the yield of product 3aa (Table
1, entries 9−11). When the base was replaced with 4Å
molecule sieves (4ÅMS), 3aa was also obtained in 59%
yield (Table 1, entry 12). A slightly larger yield was
obtained when using 3ÅMS (Table 1, entry 13). The
effect of reaction temperature on the yield of 3aa was
also examined (Table 1, entries 13−17). It was found
that an 84% yield of product 3aa was obtained when
the reaction ran at 70 °C for 36 h while lower or
higher temperature decreased the yield. Reducing the
amounts of 3ÅMS to 400 mg afforded product 3aa in
80% yield while 200 mg of 3ÅMS resulted in a
decreased yield of 3aa to 75% (Table 1, entries 18-
19). No desired product was observed without 3ÅMS
or a base at 70 °C even for 72 h, but 15% yield of 3aa
was obtained at 100 °C for 36 h (Table 1, entries
20−22). These results revealed that 3ÅMS definitely
promoted the O-arylation process. Hence, the optimal
conditions for O-arylation were using 3ÅMS at 70 °C
in DCE for 36 h.
prepare
diverse
functionalized
2-substituted
benzoxazoles by selective O-arylation and sequential
[3,3]-rearrangement from available amidoximes,
which were easily prepared by nitriles and
hydroxylamine.
Table 1. Optimization of the O-arylation reaction.a
O Ph
NH2
OH
N
N
conditions
A) Common strategies to synthesize 2-substituted benzoxazoles
+
Ph2IOTf
O
Pd/Cu/Co/Fe
Ph
Ph
NH2
H
RX
N
1a
2a
3aa
X = halide, B(OH)2
entry solvent
additive
T (°C)
yield (%)b
61
39
53
50
30
39
33
35
57
60
53
59
62
60
77
84
OH
O
N
RCOOH/RCHO/RCOCl
1
DCE
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuONa
Cs2CO3
NEt3
4ÅMS
3ÅMS
3ÅMS
3ÅMS
3ÅMS
3ÅMS
3ÅMS
3ÅMS
-
80
80
80
80
80
80
80
80
80
80
80
80
80
100
75
70
60
70
70
70
80
100
R
NH2
2
3
4
5
toluene
MeCN
MeOH
THF
X
O
Cu/Pd/Ni
X = H, halides
N
H
R
B) Kürti's work, TM-free O-arylation and [3,3]-rearrangement to prepare benzofurans
6
7
8
9
dioxane
DMF
DMSO
DCE
OH
O
Ar
N
N
t-BuOK
DMF
HCl
H2O
R1
R
Ar2IX
+
O
R
R
30 examples
57-92% yields
40 examples
40-90% yields
10
11
12
13
14
15
16
17
18
19
20
21
22
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
C) Olofsson's work, TM-free O-arylation and [3,3]-rearrangement to prepare benzofurans
O
OH
O Ar
t-BuONa
MeCN
N
N
R
R1
Ar2IX
R
+
HCl / H2O
O
EtO
EtO
12 examples
50-82% yields
D) This work, TM-free selective O-arylation and [3,3]-rearrangement to prepare benzoxazoles
OH
O
Ar
O
N
N
N
Ar2IOTf
base-free
73
acid
R1
R
80c
75d
-
R
NH2
R
NH2
+
NH2OH
RCN
-
-
5
15
DCE
Scheme 1. Synthesis of Heterocyclic Compounds.
2
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10.1002/adsc.201700906
Advanced Synthesis & Catalysis
a)
Conditions: 1a (0.3 mmol), 2a (0.6 mmol, 2.0 equiv),
good yields (Table 3). The arylamidoximes were
tolerated electron-donating or electron-withdrawing
groups with para, meta, and ortho substituents (Table
3, 3ba-ja). Pleasingly, heteroaryl groups such as
pyridinyl, and thienyl groups gave product 3ka and
3la in 50% and 65% yields, respectively.
Styrenylamidoxime 1m reacted with 2a to furnish the
desired product 3ma in 65% yield. When the R group
in 1 was presented with alkyl groups, iso-propyl
substituted 1o gave 3oa in better yield than methyl-
or piperidinyl-substituted 1n or 1p (Table 3, 3oa-pa).
It is worthy to note that amidoxime 1q with an ester
group could also provide O-arylation product 3qa in
46% yield. In all cases, no N-arylation products were
observed in the crude mixtures, which revealed that
the selective O-arylation of various aldoximes could
be controlled.
additive (0.6 mmol or 600 mg for MS), solvent (3 mL),
18−72 h; b) isolated yields; c) 400 mg for 3ÅMS; d) 200 mg
for 3ÅMS.
To explore the scope and functional group
tolerance of the O-arylation process, a variety of
diaryliodonium salts 2 were subjected to the
optimized O-arylation conditions. As shown in Table
2, diaryliodonium salts with electron-donating or
electron-withdrawing groups bearing para, meta, or
ortho-substituents provided the desired O-arylation
product 3 in moderate to excellent yields. However,
the iodonium salt 2b with a para-methoxy group did
not afford the product 3ab easily (Table 2, entry 2).
The iodonium salts containing electron-withdrawing
groups gave better yields than those with the
electron-donating groups (Table 2, entries 2−4 vs
5−7). When asymmetric diaryliodonium salts were
used, the electron-deficient aryl moieties were
preferably transferred to the desired products (Table 2,
entries 12−17). The reaction was tolerated by certain
sensitive functional groups, such as halides and nitro,
ester, and aldehyde groups, which will enable more
transformations by further functionalization.
Table 3. The scope of amidoximes 1.a,b
OH
O Ph
3ÅMS
N
N
+
Ph2IOTf
DCE, 70 °C
R
NH2
R
NH2
Cl
1
2a
3
O
Ph
O
Ph
O
Ph
X = 4-MeO, 3ba, 74%
X = 4-Me, 3ca, 71%
X = 4-t-Bu,
X = 4-Cl, 3ea, 72%
X = 4-F, 3fa, 65%
X = 4-CF3, 3ga, 55%
N
N
N
3da
, 64%
NH2
NH2
NH2
Me
3ha, 79%
Cl
X
3ia, 71%
Table 2. The scope of diaryliodonium salt 2.a
O
Ph
O
Ph
O
Ph
N
N
O
Ph
N
N
R1
O
O
NH2
NH2
NH2
OH
O
I
OTf
R2
Ph
NH2
N
N
3ÅMS
S
N
+
R1
3ka, 50%
Ph
3la, 65%
3ma, 65%
DCE, 70 °C
3ja, 69%
Ph
NH2
Ph
NH2
O
O
Ph
O
Ph
N
N
O
N
Ph
N
1a
2
3aa
Me
N
NH2
, 81%
Me
NH2
NH2
3pa, 31%
MeO2C
NH2
3qa, 46%
Me
entry
1
2
3
4
5
6
7
8
R1
H
4-MeO
4-Me
4-t-Bu
4-Cl
R2
H
4-MeO
4-Me
4-t-Bu
4-Cl
yield (%)b
84
<5
51
50
2
3
3na
3oa
, 40%
a)
2a
2b
2c
2d
2e
2f
3aa
3ab
3ac
3ad
3ae
3af
Conditions: 1 (0.3 mmol), 2a (0.6 mmol, 2.0 equiv),
b)
3ÅMS (600 mg), solvent (3 mL), 12−72 h;
isolated
yields.
84
85
4-F
4-F
With diverse O-arylation product 3 in hand, we
attempted to explore its tautomerization/[3,3]-
rearrangement sequence to synthesize 2-substituted
benzoxazoles. After extensive optimization of the
reaction conditions, we found that the desired 2-
substituted benzoxazole 4 could be obtained in good
yield under 1.0 equiv of trifluoroacetic acid (TFA) in
CCl4 at 100 °C.[15] A variety of O-arylation products
4-CF3
3-Me
3-NO2
3,5-Me2
2-Me
4-Ph
4-Br
3-Br
2-Br
4-CF3
3-Me
3-NO2
3,5-Me2
2-Me
4-MeO
4-MeO
4-MeO
4-MeO
H
86
62
88
60
78
58
66
90
2g
2h
2i
2j
2k
2l
2m
2n
2o
2p
2q
3ag
3ah
3ai
3aj
3ak
3al
3am
3an
3ao
3ap
3aq
9
10
11
12
13
14
15
16
3
were then successfully converted to the
80
93
92
corresponding 2-substituted benzoxazoles under
TFA-mediated conditions in moderate to good yields
(Table 4). The electron-donating groups presented on
the R1 group furnished better yields than the electron-
withdrawing groups (Table 4, 4aa-al). In particular,
O-arylation product 3ag with a CF3 group proceeded
at 140 °C to give the rearrangement product 4ag in 30%
yield. Interestingly, when R1 of O-arylation product 3
was a meta-substituent, the regioselectivity of the
[3,3]-rearrangement depended on the substituted
groups. The methyl group gave a 1.6:1 ratio of
product 4ah in 99% yield, while the bromo group
4-CO2Me
4-CHO
17
H
a)
Conditions: 1a (0.3 mmol), 2 (0.6 mmol, 2.0 equiv),
b)
3ÅMS (600 mg), solvent (3 mL), 12−72 h;
yields.
isolated
Next, the scope of amidoximes was also evaluated
for the O-arylation protocol. Various amidoximes
containing aryl, heteroaryl, alkenyl, alkyl, as well as
ester groups afforded the O-arylation products in
3
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10.1002/adsc.201700906
Advanced Synthesis & Catalysis
1) Radical trapping experiment
gave a 20:1 ratio of product 4an in 19% yield only.
The aryl amidoximes with electron-donating or
electron-withdrawing groups did not affect the yield
of rearrangement products much (Table 4, 4ba-ga).
Both thienyl and styrenyl substituted O-arylated
amidoximes 3la and 3ma gave desired products in
moderate yields (Table 4, 4la-ma). 2-Ester
substituted benzoxazole 4qa was obtained in 31%
yield, which allowed the functionalized benzoxazole
to undergo more transformations easily. However, the
alkyl-substituted O-arylated amidoximes 3na and 3oa
in Table 3 could not afford the corresponding
benzoxazoles 4na and 4oa under the optimal
conditions, perhaps because of these compounds
containing ɑ-H on the carbon-atoms.
O
N
O
TFA
Ph
N
CCl4, 100 °C
Ph
NH2
3aa
TEMPO (1.0 equiv)
4aa
80%
2) controlled crossing experiment
O
O
O
Me
Ph
N
OMe
N
Me
N
Ph
NH2
TFA
4ba
, 63%
4ac, 95%
3ac
CCl4, 100 °C
O
Ph
+
O
N
N
O
OMe
Ph
NH2
N
Me
4aa, 0%
4bc, 0%
MeO
3ba
3ac/3ba = 1:1
Scheme 2. Mechanistic Studies.
Table 4. The scope of the [3,3] rearrangement.a, b
Based on the controlled experimental results, a
possible mechanism for formation of benzoxazole
4aa from amidoxime 1a and diaryliodonium salts 2a
was proposed. As shown in Scheme 3, the reaction of
amidoxime 1a with iodonium salt 2a can generate
intermediate A, which can undergo 1,2-phenyl
migration to give the O-arylation product 3aa.[16]
Compound 3aa tautomerizes to intermediate B under
TFA, which undergoes a [3,3]-rearrangement to
provide intermediate C. Intramolecular cyclization of
intermediate C can give intermediate D, which can
furnish the target product 4aa by elimination.
O
O
N
TFA (1.0 equiv)
CCl4, 100 °C
N
R1
R
R1
R
NH2
4
3
R1 = H, 4aa, 82%
R1 = Me, 4ac, 83%
R1 = t-Bu, 4ad, 96%
R1 = Cl, 4ae, 62%
R1 = Br, 4am, 71%
R1 = F, 4af, 75%
R1 = CF3, 4ag, 30%c
R1 = Ph, 4al, 77%
R1
O
N
O
Ph
+
O
Ph
N
Ph
R1
R1
N
b
a
R1 = Me, 4ah, 99% (a:b = 1.6:1)d
R1 = Br, 4an, 19% (a:b = 20:1)d
O
Me
Me
X
Br
O
N
Ph
O
O
N
X = OMe, 4ba, 60%
X = Me,
X = t-Bu, 4da, 79%
X = Cl, 4ea, 71%
X = CF3, 4ga, 67%
Ph
N
Ph
4ca
, 64%
N
Me
4aj
Ph
O
I Ph
OH
, 80%
4ak, 63%
4ao, 68%
Cl
O
1,2-migration
PhI
2a
Ph2IOTf,
HOTf
N
N
N
O
Me
Ph
NH2
Ph
NH2
Ph
NH2
O
O
N
O
N
O
Cl
3aa
1a
A
N
4ha, 54%
4ia, 70%
4ja, 56%
TFA
O
N
O
O
S
O
N
CO2Et
R
H
Ph
N
O
N
H+
condensation
H
HO
HN
O
H2N
[3,3]
N
4aa
4la, 48%
4ma, 54%
R = Me, 4na, 0%
4oa
4qa, 31%
R = i-Pr,
, 0%
Ph
N
NH
Ph
NH
H
a)
Ph
Conditions: 3 (0.2 mmol), TFA (0.2 mmol, 1.0 equiv),
NH4
D
C
B
CCl4 (2 mL), 100 °C, 12−72 h; b) isolated yields; ran at
c)
140 °C; d) regioselectivity of the [3,3]-rearrangement.
Scheme 3. Proposed Mechanism.
To investigate the reaction mechanism, control
experiments were performed. When compound 3aa
reacted with TEMPO (1.0 equiv) under the optimal
conditions, product 4aa was isolated in 80% yield,
which suggested the [3,3]-rearrangement might not
involve a radical process (Scheme 2-1). A mixture of
3ac and 3ba with a 1:1 ratio was subjected into the
TFA-mediated conditions; no desired crossing
products 4ba and 4bc were observed and only
products 4ac and 4aa were obtained in 95% and 63%
yields, respectively (Scheme 2-2). This result further
revealed that the reaction was an intramolecular
rearrangement process.
As O-arylation is highly selective for amidoximes
containing two nucleophilic sites, we tested
amidoxime 1r bearing three nucleophilic sites
(Scheme 4-1). When 1r reacted with 2a under
optimal conditions, the O-arylation product 3ra was
obtained in 78% yield. However, compound 3ra
could not undergo [3,3]-rearrangement to give
benzoxazole 4ra under TFA-mediated conditions.
Interestingly, benzoxazole 4sa was obtained in 54%
yield under the optimal conditions by an initial
acetyl-protection of 3ra to compound 3sa. To further
explore the efficiency of this O-arylation and [3,3]-
rearrangement sequence, a commercial amidoxime 5
was used (Scheme 4-2). O-arylation of 1.94 g of
amidoxime 5 with 2a afforded compound 6 in 64%
yield (2.2 g), which converted to 1.03 g of a bidentate
4
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10.1002/adsc.201700906
Advanced Synthesis & Catalysis
eluents (1: 20 ethyl acetate: petroleum ether to 1: 10) to
N-ligand 7 in 54% yield under the TFA-mediated
provide product 4aa (0.032 g, 82%) as a white solid. Mp:
conditions.[17]
1
95−96 °C; H NMR (400 MHz, CDCl3): δ 8.18−8.16 (m,
2H), 7.70−7.68(m, 1H), 7.49−7.47(m, 1H), 7.43−7.42 (m,
3H), 7.27−7.24 (m, 2H); 13C NMR (125 MHz, CDCl3): δ
163.1, 150.8, 142.1, 131.5, 128.9, 127.6, 127.2, 125.1,
124.6, 120.0, 110.6; IR (thin film) 3403, 2925, 1614, 1449,
1343, 1189, 743 cm−1; HRMS (ESI) m/z calcd for
C13H10NO (M+H)+ 196.0762, found 196.0750.
1) Testing of amidoxime 1r containing three nucleophilic sites
O
Ph
OH
N
N
TFA
0%
O
N
Ph2IOTf
NH2
NH2
NH2
3ÅMS, 70 °C
78%
H2N
H2N
3ra
4ra
1r
CH3COCl
90%
Acknowledgements
O
Ph
N
O
N
TFA
NH
O
NH2
54%
Financial support from the “Overseas 100 Talents Program” of
Guangxi Higher Education, National Natural Science
Foundation of China (21562005, 21602037), State Key
Laboratory for Chemistry and Molecular Engineering of
Medicinal Resources, Ministry of Science and Technology of
China (CMEMR2015-A05), and Natural Science Foundation of
Guangxi (2015GXNSFCA139001, 2016GXNSFFA380005) are
greatly appreciated. We also thank Dr. Christina M. Jones, from
Liwen Bianji, Edanz editing China (www.liwenbianji.cn/ac), for
the manuscript proofreading.
O
Me
Me
N
H
4sa
3sa
7
2) Gram-scalable preparation of N-ligand
H2N
NH2
O
O
H2N
HO
NH2
OH
Ph2IOTf
TFA
N
N
N
N
3ÅMS, 70 °C
64%
CCl4, 100 °C
54%
N
N
O
O
Ph
Ph
5
6
7
1.03 g, 3.3 mmol
1.94 g, 10 mmol
2.20 g, 6.4 mmol
Scheme 4. Applications of the Selective O-Arylation and
[3,3]-Rearrangement Strategy
References
[1] a) S. Noël, S. Cadet, E. Gras, C. Hureau, Chem. Soc.
Rev. 2013, 42, 7747; b) Z. Jin, Nat. Prod. Rep. 2011, 28,
1143.
In summary, we developed a metal-free strategy to
prepare
diverse
functionalized
2-substituted
benzoxazoles by a sequence of O-arylation and [3,3]-
rearrangement from amidoximes and diaryliodonium
salts. The reaction underwent base-free selective O-
arylation of amidoximes giving O-arylation products
and TFA-mediated [3,3]-rearrangement to give
functionalized 2-substituted benzoxazoles. This
method features selective O-arylation, good
functional group tolerance, broad substrate scopes
and gram-scalable preparations.
[2] Some examples of benzoxazoles in drug discovery, see:
a) R. N. Brown, R. Cameron, D. K. Chalmers, S.
Hamilton, A. Luttick, G. Y. Krippner, D. B. McConnell,
R. Nearn, P. C. Stanislawski, S. P. Tucker, K. G.
Watson, Bioorg. Med. Chem. Lett. 2005, 15, 2051; b) E.
S. Manas, R. J. Unwalla, Z. B. Xu, M. S. Malamas, C.
P. Miller, H. A. Harris, C. Hsiao, T. Akopain, W.-T.
Hum, K. Malakian, S. Wolfrom, A. Bapat, R. A. Bhat,
M. L. Stahl, W. S. Somers, J. C. Alvarez, J. Am. Chem.
Soc. 2004, 126, 15106; c) D. L. Boger, H. Miyauchi, M.
P. Hedrick, Bioorg. Med. Chem. Lett. 2001, 11, 1517; d)
B. Gong, F. Hong, C. Kohm, L. Bonham, P. Klein,
Bioorg. Med. Chem. Lett. 2004, 14, 1455; e) L.-Q. Sun,
J. Chen, M. Bruce, J. A. Deskus, J. R. Epperson, K.
Takaki, G. Johnson, L. Iben, C. D. Mahle, E. Ryan, C.
Xu, Bioorg. Med. Chem. Lett. 2004, 14, 3799; f) M. S.
Malamas, E. S. Manas, R. E. McDevitt, I. Gunawan, Z.
B. Xu, M. D. Collini, C. P. Miller, T. Dinh, R. A.
Henderson, J. C. Keith Jr., H. A. Harris, J. Med. Chem.
2004, 47, 5021.
Experimental Section
General procedure for synthesis of 3aa: In a Schlenk
tube was charged with amidoxime 1a (0.041 g, 0.3 mmol)
under an air atmosphere, dissolved in DCE (3 mL) and
3ÅMS (0.600 g) was added in one portion at room
temperature. The mixture was stirred vigorously at room
temperature for 2 min. Then, diaryliodonium salt 2a (0.258
g, 0.60 mmol, 2.0 equiv) was added in one portion. The
reaction was stirred at 70 °C and monitored by TLC until
1a was consumed completely (36 h). At this time, the DCE
was removed under reduced pressure and the crude product
was purified by flash chromatography (dry loading with
SiO2) using eluents (1: 20 ethyl acetate: petroleum ether to
1: 1) to provide product 3aa (0.054 g, 84%) as a white
[3] a) L. Leventhal, M. R. Brandt, T. A. Cummons, M. J.
Piesla, K. E. Rogers, H. A. Harris, Eur. J. Pharmacol.
2006, 553, 146; b) J. Nishiu, M. Ito, Y. Ishida, M.
Kakutani, T. Shibata, M. Matsushita, M. Shindo,
Diabetes, Obes. Metab. 2006, 8, 508; c) J. Easmon, G.
Pürstinger, K.-S. Thies, G. Heinisch, J. Hofmann, J.
Med. Chem. 2006, 49, 6343; d) K. Rasmussen, M.-A.
Hsu, Y. Yang, Neuropsychopharmacology 2007, 32,
786; e) I. H. Leaver, B. Milligan, Dyes Pigm. 1984, 5,
109; f) C. A. Baxter, E. Cleator, K. M. J. Brands, J. S.
Edwards, R. A. Reamer, F. J. Sheen, G. W. Stewart, N.
A. Strotman, D. J. Wallace, Org. Process Res. Dev.
2011, 15, 367.
1
solid. Mp: 156−157 °C; H NMR (400 MHz, CDCl3): δ
7.65 (d, J = 6.8 Hz, 2H), 7.39−7.31 (m, 3H), 7.25−7.21 (m,
4H), 6.90−6.88 (m, 1H), 4.98 (s, 2H); 13C NMR (100 MHz,
CDCl3): δ 159.5, 153.9, 131.9, 130.4, 129.2, 128.7, 126.2,
121.5, 114.4; IR (thin film) 3458, 2924, 1630, 1488, 1227,
1157, 917, 749 cm−1; HRMS (ESI) m/z calcd for
C13H13N2O (M+H)+ 213.1028, found 213.1008.
General procedure for synthesis of 4aa: In a Teflon-
sealed flask was charged with 3aa (0.042 g, 0.20 mmol)
under an air atmosphere, dissolved in CCl4 (2 mL) and
TFA (0.015 mL, 0.20 mmol, 1.0 equiv) was added in one
portion at room temperature. The reaction vessel was
sealed with a Teflon cap and stirred vigorously at room
temperature for 2 min. Then, the reaction was stirred at
100 °C for 35 h. At this time, the CCl4 was removed under
reduced pressure and the crude product was purified by
flash chromatography (dry loading with SiO2) using
[4] For a general overview of synthetic methods to
benzoxazoles, see: G. V. Boyd, In Science of Synthesis:
5
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10.1002/adsc.201700906
Advanced Synthesis & Catalysis
Houben-Weyl Methods of Molecular Transformations:
E. Schaumann, Ed.; Thieme: Stuttgart, 2002, Vol. 11,
pp 481-492.
[9] Some reviews for diaryliodonium salts, see: a) E. A.
Merritt, B. Olofsson, Angew. Chem. Int. Ed. 2009, 48,
9052; Angew. Chem. 2009, 121, 9214; b) E. A. Merritt,
B. Olofsson, Synthesis 2011, 2011, 517; c) B. Olofsson,
Top. Curr. Chem. 2015, 373, 135; d) K. Aradi, B. L.
Tóth, G. L. Tolnai, Z. Novák, Synlett 2016, 27, 1456; e)
M. Fañanás-Mastral, Synthesis 2017, 49, 1905.
[5] Selected recent examples, see: a) L. Liu, L.-W. Qian, S.
Wu, J. Dong, Q. Xu, Y. Zhou, S.-F. Yin, Org. Lett.
2017, 19, 2849; b) T. Gieshoff, A. Kehl, D.
Schollmeyer, K. D. Moeller, S. R. Waldvogel, Chem.
Commun. 2017, 53, 2974; c) C. Sen, T. Sahoo, S. M.
Galani, A. B. Panda, S. C. Ghosh, ChemistrySelect
2016, 1, 2542; d) Y.-L. Lai, J.-S. Ye, J.-M. Huang,
Chem. Eur. J. 2016, 22, 5425; e) N. Aljaar, C. C.
Malakar, J. Conrad, U. Beifuss, J. Org. Chem. 2015, 80,
10829; f) X. Chen, F. Ji, Y. Zhao, Y. Liu, Y. Zhou, T.
Chen, S.-F. Yin, Adv. Synth. Catal. 2015, 357, 2924; g)
Y. H. Cho, C.-Y. Lee, D.-C. Ha, C.-H. Cheon, Adv.
Synth. Catal. 2012, 354, 2992; h) W.-C. Li, C.-C Zeng,
L.-M. Hu, H.-Y. Tian, R. D. Little, Adv. Synth. Catal.
2013, 355, 2884; i) W.-J. Yoo, H. Yuan, H. Miyamura,
S. Kobayashi, Adv. Synth. Catal. 2011, 353, 3085.
[10] Selected examples of O-arylation and [3,3]-
rearrangement sequence, see: a) T. J. Maimone, S. L.
Buchwald, J. Am. Chem. Soc. 2010, 132, 9990; b) N.
Takeda, M. Ueda, S. Kagehira, H. Komei, N. Tohnai,
M. Miyata, T. Naito, O. Miyata, Org. Lett. 2013, 15,
4382; c) K. Miyagi, K. Moriyama, H. Togo,
Heterocycles 2014, 89, 2122; d) T. Tomakinian, C.
Kouklovsky, G. Vincent, Synlett 2015, 26, 1269; e) Z.-
X. Wang, W.-M. Shi, H.-Y. Bi, X.-H. Li, G.-F. Su, D.-
L. Mo, J. Org. Chem. 2016, 81, 8014; f) W.-M. Shi, X.-
P. Ma, C.-X. Pan, G.-F. Su, D.-L. Mo, J. Org. Chem.
2015, 80, 11175.
[6] a) S. Zhang, Y.-H. Niu, X.-S. Ye, Org. Lett. 2017, 19,
3608; b) Y. Li, M. Wang, W. Fan, F. Qian, G. Li, H. Lu,
J. Org. Chem. 2016, 81, 11743; c) S. Yamada, K.
Murakami, K. Itami, Org. Lett. 2016, 18, 2415; d) F.
Hu, J. Yang, Y. Xia, C. Ma, H. Xia, Y. Zhang, J. Wang,
Organometallics 2016, 35, 1409; e) F. Zhu, J.-L. Tao,
Z.-X. Wang, Org. Lett. 2015, 17, 4926; f) L.
Ackermann, S. Barfusser, J. Pospech, Org. Lett. 2010,
12, 724; g) C. M. Filloux, T. Rovis, J. Am. Chem. Soc.
2015, 137, 508; h) M. Corro, M. Besora, C. Maya, E.
Alvarez, J. Urbano, M. R. Fructos, F. Maseras, P. J.
Perez, ACS Catal. 2014, 4, 4215; i) R. S. Sánchez, F. A.
Zhuravlev, J. Am. Chem. Soc. 2007, 129, 5824.
[11] H. Gao, Q.-L. Xu, C. Keene, L. Kürti, Chem. Eur. J.
2014, 20, 8883.
[12] R. Ghosh, E. Stridfeldt, B. Olofsson, Chem. Eur. J.
2014, 20, 8888.
[13] Some examples for metal and ligand controlled
selectivity for multiple nucleophiles, see: a) A. Shafir,
P. A. Lichtor, S. L. Buchwald, J. Am. Chem. Soc. 2007,
129, 3490; b) D. Mati, S. L. Buchwald, J. Am. Chem.
Soc. 2009, 131, 17423; c) G. O. Jones, P. Liu, K. N.
Houk, S. L. Buchwald, J. Am. Chem. Soc. 2010, 132,
6205; d) M. Rovira, M. Soler, I. Güell, M.-Z. Wang, L.
Gómez, X. Ribas, J. Org. Chem. 2016, 81, 7315; e) T.
Xu, H. Alper, J. Am. Chem. Soc. 2014, 136, 16970.
[7] a) J. Jiang, H. Zou, Q. Dong, R. Wang, L. Lu, Y. Zhu,
W. He, J. Org. Chem. 2016, 81, 51; b) C. S. Cho, D. T.
Kim, J. Q. Zhang, S.-L. Ho, T.-J. Kim, S. C. Shim, J.
Heterocycl. Chem. 2002, 39, 421; c) J. Chang, K. Zhao,
S. Pan, Tetrahedron Lett. 2002, 43, 951; d) R. S.
Pottorf, N. K. Chadha, M. Katkevics, V. Ozola, E. Suna,
H. Ghane, T. Regberg, M. R. Player, Tetrahedron Lett.
2003, 44, 175; e) W. Chen, W. An, Y. Wang, A. Yu, J.
Org. Chem. 2016, 81, 10857; f) J. A. Garduño, J. J.
García, ACS Catal. 2015, 5, 3470; g) M. S. Mayo, X.
Yu, X. Zhou, X. Feng, Y. Yamamoto, M. Bao, J. Org.
Chem. 2014, 79, 6310.
[14] a) X.-P. Ma, W.-M. Shi, X.-L. Mo, X.-H. Li, L.-G. Li,
C.-X. Pan, B. Chen, G.-F. Su, D.-L. Mo, J. Org. Chem.
2015, 80, 10098; b) S.-Y. Wu, X.-P. Ma, C. Liang, D.-
L. Mo, J. Org. Chem. 2017, 82, 3232; c) W.-M. Shi, F.-
P. Liu, Z.-X. Wang, H.-Y. Bi, C. Liang, L.-P. Xu, G.-F.
Su, D.-L. Mo, Adv. Synth. Catal. 2017, 359, 2741.
[15] The equivalents of TFA were also optimized. 4aa was
obtained in 23% yield (0.1 equiv of TFA), 48% yield
(0.2 equiv of TFA), 65% yield (0.3 equiv of TFA); 75%
yield (0.5 equiv of TFA). Other types of acids were
also examined, please see more details for the
optimization of [3,3]-rearrangement in Supporting
Information.
[8] a) G. Evindar, R. A. Batey, J. Org. Chem. 2006, 71,
1802; b) S. Ueda, H. Nagasawa, Angew. Chem. Int. Ed.
2008, 47, 6411; Angew. Chem. 2008, 120, 6511; c) J. I.
Urzúa, R. Contreras, C. O. Salas, R. A. Tapia, RSC Adv.
2016, 6, 82401; d) J. Peng, C. Zong, M. Ye, T. Chen, D.
Gao, Y. Wang, C. Chen, Org. Biomol. Chem. 2011, 9,
1225; e) V. Kavala, D. Janreddy, M. J. Raihan, C.-W
Kuo, C. Ramesh, C.-F. Yao, Adv. Synth. Catal. 2012,
354, 2229; f) S. K. Alla, P. Sadhu, T. Punniyamurthy, J.
Org. Chem. 2014, 79, 7502; g) J. Sedelmeier, F. Lima,
A. Litzler, B. Martin, F. Venturoni, Org. Lett. 2013, 15,
5546.
[16] An example for [1,2]-phenyl migration of iodonium
salts, see: P.-O. Nobby, T. B. Petersen, M. Bielawski, B.
Olofsson, Chem. Eur. J. 2010, 16, 8251.
[17] Selected example for the bidentate N-ligand, see: A.
K.-W. Chan, E. S.-H. Lam, A. Y.-Y. Tam, D. P.-K.
Tsang, W. H. Lam, M.-Y. Chan, W.-T. Wong, V. W.-
W. Yam, Chem. Eur. J. 2013, 19, 13910.
6
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10.1002/adsc.201700906
Advanced Synthesis & Catalysis
COMMUNICATION
Base-Free Selective O-Arylation and Sequential
[3,3]-Rearrangement of Amidoximes with
Diaryliodonium Salts: Synthesis of 2-Substituted
Benzoxazoles
OH
O
Ar
N
O
N
Ar2IOTf
TFA
R1
R
base-free
CCl4, 100 °C
NH2
R
NH2
R
N
Adv. Synth. Catal. Year, Volume, Page – Page
. Base-free selective O-arylation
O
N
O
. Good functional group tolerance
. Broad substrate scope
N
Wei-Min Shi, Xiao-Hua Li, Cui Liang, and Dong-
Liang Mo*
. Gram-scalable preparations
1.03 g, Two steps
7
This article is protected by copyright. All rights reserved.