TEMPO-mediated C-H amination of benzoxazoles with N-heterocycles

Article abstract of DOI:10.1021/acs.joc.0c01921

The direct amination of benzoxazoles at C2 using N-heterocycles as nitrogen sources has been developed for the first time. Several kinds of inexpensive oxidants and also electricity were effective for this transformation in the presence of 2,2,6,6- tetram

Full text of DOI:10.1021/acs.joc.0c01921

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Note
TEMPO-Mediated C-H Amination of Benzoxazoles with N-Heterocycles
Jian Wang, Jiang-Hua Li, Yidong Guo, Hongbo Dong, Qiang Liu, and Xiao-Qi Yu
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.0c01921 • Publication Date (Web): 03 Sep 2020
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The Journal of Organic Chemistry
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TEMPO-Mediated C-H Amination of Benzoxazoles with N-Heterocycles
Jian Wang,† Jiang-Hua Li,† Yidong Guo,† Hongbo Dong,† Qiang Liu*,‡ and Xiao-Qi Yu*,§
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†Sichuan Industrial Institute of Antibiotics, Chengdu University, Chengdu 610052, China
‡College of Chemistry and Environmental Protection Engineering, Southwest Minzu University, Chengdu 610041,
China
E-mail: lqchem@163.com
§Key Laboratory of Green Chemistry and Technology, Ministry of Education, College of Chemistry, Sichuan University,
Chengdu 610064, China
E-mail: xqyu@scu.edu.cn
ABSTRACT: The direct amination of benzoxazoles at C2 using N-heterocycles as nitrogen sources has been developed for the
first time. Several kinds of inexpensive oxidants and also electricity were effective for this transformation in the presence of
TEMPO. This metal-free and operationally simple reaction can afford a variety of important C,N`-linked bis-heteocycles in
moderate to good yields under very mild reaction conditions. The in situ generated oxoammonium salt had been proved to
be important for this transformation.
Oxazole and their derivatives are privileged synthetic scaf-
folds due to their useful biological properties, and applica-
tion as important building blocks for functional materials.1
During the past decades, remarkable progresses have been
made to develop efficient methods for their synthesis. In
particular, the construction of C-N bonds through coupling
reaction between C-H bond at the 2-position of oxazole and
various nitrogen sources under transition-metal catalysis
or metal-free conditions have attracted significant research
interest (Scheme 1).2 Among all these reported protocols
for the direct C-H amination of oxazole, secondary amines
were the most used nitrogen sources.3 Primary amines and
ammonia usually participated in the amination of oxazole
under relatively milder conditions in comparison with sec-
ondary amines.3f,4 Anilines generally showed lower activity
than secondary amines during this amination, and therefore
metal catalysts were commonly employed to active anilines
through organometal intermediate.3e,5 Formamides3f,6 and
tertiary amines7 were able to be utilized as nitrogen sources
in a one-pot domino fashion began with the dissociation of
the strong C-C bonds under harsh conditions. Direct ami-
dation of oxazole with amides was also successfully realized
through a copper-mediated aerobic coupling reaction at
high temperature.8 Electrophilic amination reagent such as
chloroamines9 and O-acylated hydroxylamines10 have been
introduced as nitrogen sources, in which case external oxi-
dant can be avoided.
Scheme 1. Direct C-H amination of oxazole
Despite great achievements, N-heterocycles are still un-
developed to couple with oxazole directly using reported
methods. The bis-heteocycles consist of oxazole and N-het-
erocycles are biologically important,11 and the method of
connecting these two parts directly is highly desired. Herein,
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we report the firstdirect amination of benzoxazoles at C2
Page 2 of 7
benzoxazoles with secondary amines (Scheme 1).3b How-
ever, N-heterocycles was not reported here as nitrogen
sources. N-heterocycles show lower activity than secondary
amines during this kind of amination reactions, which was
supported by our previous work3g and Little`s report3d. Ben-
zoxazole may decompose in the presence of abundant
TEMPO+ when N-heterocycles are unable to attack benzox-
azole quickly. The in-situ generation of TEMPO+ may ad-
dress this problem. Only TEMPO cannot trigger this oxida-
tive reaction although TMEPO own some oxidizing property
(entry 1). So, we began to screen a lot of oxidants in the
presence of stoichiometric TEMPO. When the relatively
strong oxidants were used, moderate yields of cross-cou-
pling product 3a were obtained (entries 2–5). Conditions
with milder oxidant NCS (N-Chlorosuccinimide) can also
form the product (entry 6). We found PhI(OAc)2 was the
best oxidant which can gave 86% yield together with
TEMPO (entry 7). The quantity of TEMPO and PhI(OAc)2
cannot be reduced or the yield will decreased significantly
(entries 8–11). It has been known that PhI(OAc)2 is a typical
secondary oxidant in the TEMPO-involved oxidation reac-
tions which usually go through classical oxoammonium cat-
ion mechanism.15 Therefore, we used one stable oxoammo-
nium salt (Bobbitt`s Salt) to oxidize the starting materials
directly, but only achieved a low yield (entry 12). Consider-
ing the merit of electrochemical methods in organic synthe-
sis and the widely use of TEMPO in electrochemical
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using N-heterocycles as nitrogen sources under metal-free
conditions.
In our previous work, we had demonstrated that FeCl3
could mediate direct amination of azoles using formamides
or amines as nitrogen sources in air (Scheme 1).3g N-heter-
ocycles such as imidazole worked as ligand instead of nitro-
gen sources in this reaction. Therefore, we want to know
whether the N-heterocycles could work as nitrogen sources
to couple with oxazole. Inspired by the report of Nicewicz
and coworkers,12 pyrazoles have been widely used as nitro-
gen sources in the direct amination of C-H bonds.13 Here we
used pyrazole as a representative N-heterocyclic nitrogen
source to react with benzoxazole. The results of reaction op-
timization are summarized in Table 1. Recently, TEMPO
(2,2,6,6-tetramethyl-piperidine-N-oxyl) frequently ap-
peared in the intramolecular oxidative C-H/N-H coupling
reactions due to its versatile catalytic ability, such as hydro-
gen abstraction, single or double electron transfer, and trap-
ping of active radical.14 Therefore, we envisioned that the
combination of TEMPO and external oxidant would also be
a utility redox system for intermolecular oxidative cross-
coupling reactions. Studer and co-workers reported using
TEMPO+BF4— as organic oxidant in direct amination of
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Table 1. Optimization of the reaction conditionsa
Scheme 2. Scope of Benzoxazoles Compoundsa
yield
(%)
0
entry
oxidant (equiv)
None
additive (equiv)
1
2
TEMPO (1.0)
TEMPO (1.0)
TEMPO (1.0)
TEMPO (1.0)
TEMPO (1.0)
TEMPO (1.0)
TEMPO (1.0)
TEMPO (0.5)
TEMPO (0.5)
TEMPO (0.5)
TEMPO (0)
K2S2O8 (2.0)
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43
57
48
15
86
73
45
48
trace
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38
0
3
(NH4)Ce(NO3)6 (2.0)
Selectfluor (2.0)
NFSI (2.0)
4
5
6
NCS (2.0)
7
PhI(OAc)2 (2.0)
PhI(OAc)2 (2.0)
PhI(OAc)2 (1.2)
PhI(OAc)2 (2.0)
PhI(OAc)2 (2.0)
Bobbitt`s Salt (2.0)
Pt(+) - Pt(-), 1.2 V
Pt(+) - Pt(-), 1.5 V
Pt(+) - Pt(-), 1.2 V
Pt(+) - Pt(-), 1.2 V
RVC(+) - RVC(-), 1.2 V
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9
10b
11
12c
13d
14d
15e
16f
17d
None
TEMPO (2.0)
TEMPO (2.0)
TEMPO (2.0)
TEMPO (2.0)
TEMPO (2.0)
9
24
aReaction conditions: 1a (0.5 mmol), 2a (1.0 mmol),
c
DCE (1 mL), rt, Air, 48 h. bpyrazole (0.6 mmol). In
CH3CN (1 mL). d-fConstant cell potential, 1a (0.5 mmol),
2a (2.0 mmol), CH3CN (2 mL), rt, Air, 120 h, undivided
cell. dBu4NI (1.0 mmol) was used as supporting electro-
lyte. LiClO4 was used as supporting electrolyte. NaI
was used as supporting electrolyte. Platinum plate elec-
trode (10 mm × 10 mm × 0.1 mm). RVC electrode (10
mm × 10 mm × 5 mm). RVC=Reticulated Vitreous Car-
bon.
aReaction conditions: 1 (0.5 mmol), 2a (1.0 mmol), TEMPO
(0.5 mmol), PhI(OAc)2 (1.0 mmol), DCE (1 mL), rt, Air, 48 h.
b1 (0.5 mmol), 2a (2.0 mmol), TEMPO (1.0 mmol),
PhI(OAc)2 (2.0 mmol), DCE (2 mL), rt, Air, 72 h. 1 (0.5
mmol), 2a (5.0 mmol), TEMPO (2.5 mmol), PhI(OAc)2 (5.0
e
f
c
mmol), DCE (5 mL), rt, Air, 7 d.
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Scheme 3. Scope of N-heterocycles Compoundsa
could be acquired. The electrochemical methods have been
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also tried to improve their yields, but even worse results
had been obtained. For aryl-substituted pyrazole (2r), only
very little product (3r) could be isolated and many un-
known impurities which may come from the decomposition
of 3r were formed. Imidazole did not react with benzoxa-
zole under the standard condition, but benzimidazole could
worked as nitrogen sources effectively under identical con-
ditions (3s). Several triazoles produced 41% to 64% yields
of the C-N adducts (3t-3v). 1,2,3-triazoles gave the coupling
products 3u in 1:1.2 N-regioisomeric ratio, while benzotri-
azole only formed N1 product (3v). At last, we explored
some other substrates using similar redox system. Anisole
can be aminated by pyrazole using NSFI (N-fluorobenzene-
sulfonimid) as oxidant in presence of TEMPO in 33% yield
with similar regioselectivity as reported literature.12a Sec-
ondary amines also reacted with benzoxazole to form 2-
aminated benzoxazoles in moderated yield in this standard
conditions.
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PhI(OAc)2 does not oxidize TEMPO to TEMPO+ directly,19
however, the disproportionation of TEMPO would initiate
the formation of TEMPO+.15 We also detected hydroxyamine
and oxoammonium salt by mass spectrometry in this reac-
tion (see Supporting Information). Consequently, the for-
mation of TEMPO+ in our reaction is highly possible. Fur-
thermore, the mild oxidant NCS and the low potential elec-
tricity which were not powerful enough to activate benzox-
azole and pyrazole directly, but they were effective to make
the reaction get nonnegligible yields in the presence of
TEMPO (Table 1, entry 6 and 13). Thus, the easily in situ
generated TEMPO+ which was usually regarded as one
strong oxidant should be the real oxidant during this reac-
tion. Different to using of stoichiometric Bobbitt`s Salt, the
slowly releasing of TEMPO+ in the combination of TEMPO
and PhI(OAc)2 may be the reason for the high yield.
During the research of exploiting the synthetic utility of
this reaction, when we tried to couple the by-product iodo-
benzene with 3a in one pot after the large-scale reaction in
order to acquire the arylated bis-heteocycles (Scheme 4a),
5a was isolated in 11% yield unexpectedly. We speculated
5a came from the pyrazole-4-phenyliodonium acetate (6a)
which was formed as shown in Scheme 4b, and this was sup-
ported by literature.20 The iodonium compound 6a cannot
react with 1a in the standard condition. So 6a is another
major by-product in the standard reaction, which may ac-
count for the decrease of yield in Scheme 4c and why two
equivalents of pyrazole was need in the standard reaction.
Additionally, because many other oxidants except
PhI(OAc)2 were also effective in this reaction, initially
aReaction conditions: 1 (0.5 mmol), 2a (1.0 mmol), TEMPO
(0.5 mmol), PhI(OAc)2 (1.0 mmol), DCE (1 mL), rt, Air, 48 h.
oxidation,16 electrolytic conditions were screened for this
transformation (entries 13–17). We found many factors
were important for obtaining an acceptable yield by electro-
chemical strategy, including using Bu4NI as supporting elec-
trolyte, using CH3CN as solvent, a long reaction time, and
keeping the potential not too high.17 At last, we also tried to
improve the yield by adding AcOH under Bobbitt`s Salt con-
ditions and electrolytic conditions because it was reported
that AcOH was able to active benoxazole,3c,3d but no good re-
sult could be obtained. More optimization of this electro-
chemical oxidation conditions was continued in our group.
With the optimized reaction conditions in hand (Table 1,
entry 7), the substrate scope of this transformation was fur-
ther investigated (Scheme 2). A variety of substituted ben-
zoxazoles were examined. We first investigated the benzox-
azoles with electron-donating group at the 5-position, in-
cluding methyl (1b), methoxy (1c), and tertiary butyl (1d).
They all reacted smoothly with pyrazole to delivered high
yields of products. The electron-withdrawing groups at the
same position, such as F, Cl and Br, had a very slightly unfa-
vorable effect on the yield (3e-3g). Ester, acetyl, and phenyl
group could also be tolerated, and the high yield of 94%, 91%
and 96% were obtained correspondingly (3h-3j). Nitro
group lowered the reactivity of substrate 1, and only a mod-
erate yield of product 3k was gotten. Lastly, one equivalent
of 5,5`-(hexafluoroisopropylidene)bisbenzoxazolecould re-
act with two equivalents of pyrazole successfully under a
modified condition (3l-2).
Scheme 4. Reaction of Pyrazole with PhI(OAc)2
Next, we turned to examine the scope of pyrazole deriva-
tives and similar N-heterocycles in the benchmark reaction.
A large number of analogues have been tried, and the suc-
cessful examples are summarized in Scheme 3 (unsuccess-
ful examples see Supporting Information). Obviously, the
substituent groups on pyrazole led to a general decrease of
yields (3m-3q).18 TEMPO was replaced by other nitroxides
for trying to improve the yield, but no satisfactory results
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Scheme 5. Cyclic voltammograms of 1a, 2a, 2s and 2v in
MeCN
Scheme 6. Proposed Reaction Mechanisms
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80
60
40
20
0
100
80
60
40
20
0
1a (0.1 M )
1a (0.1 M )
2a (0.1 M )
2a (0.1 M )
+
TEM PO (3m M )
+
TE M P O (3 m M )
-20
-20
0.0
0.5
1.0
1.5
2.0
2.5
0.0
0.5
1.0
1.5
2.0
2.5
8
P otential (V vs. A g/A gC l)
P otential (V vs. A g/A gC l)
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200
150
100
50
TEM P O (5 m M )
TEM P O (5 m M )
B enzim idazole (10 m M )
100
75
50
25
0
TE M P O (3 m M )
TE M P O (3m M )
1H -B enzotriazole (0.1 M )
+
Benzim idazole (10 m M )
+
1H -B enzotriazole (0.1 M )
0
-25
-50
-50
-100
0.0
0.5
1.0
1.5
2.0
2.5
0.0
0.5
1.0
1.5
2.0
2.5
P otential (V vs. A g/A gC l)
P otential (V vs. A g/A gC l)
under Bobbitt`s Salt conditions and electrolytic conditions.
The activated benzoxazole is attacked by pyrazole to form
o-hydroxyamidine compound 10. Then, TEMPO+ oxidizes
10 to radical 11, followed by deprotonation, intramolecular
cyclization, another single-electron oxidation and deproto-
nation, finally affords product 3a.
In summary, a new oxidation system for direct amination
of benzoxazoles with N-heterocycles was developed for the
first time. Only TEMPO and PhI(OAc)2 were used in this con-
venient method. A variety of important C,N`-linked bis-
heteocycles in moderate to good yields under this reaction
conditions were obtained. We have undertaken detailed in-
vestigations of the reaction mechanism, and we concluded
that the in situ generated oxoammonium salt should be the
key mediator during the whole reaction process.
activation of pyrazole by formation a highly reactive N-I
bond in pyrazole was exclude.4a
In the oxidative C-N coupling between pyrazole and aro-
matic or heteroaromatic compounds, pyrazole usually un-
dergo nucleophilic attack of radical cation intermediate of
aryl compounds which derived from single-electron oxida-
tion processes.12,13a-c To verify the possibility of single-elec-
tron oxidation during our reaction, we then studied the in-
teraction between TEMPO+ and the substrates by investi-
gating the redox behavior of them by voltammetric analysis.
As shown in Scheme 5, both benzoxazole and pyrazole dis-
played a weak irreversible oxidation wave (1a at Eox=2.27 V
vs Ag/AgCl, 2a at Eox=2.24 V vs Ag/AgCl), and they had no
interaction with TEMPO+ in the voltammetric analysis
(Scheme 5a and 5b). It means TEMPO+ cannot react with 1a
or 2a directly by single electron transfer. When we contin-
ued to check other substrates by voltammetric analysis, it
was found that benzimidazole and 1H-benzotriazole could
weaken the reduction wave of TEMPO significantly (Scheme
5c and 5d), and this indicated the quickly consumption of
the TEMPO+ from the electrode surface via reaction with
benzimidazole and 1H-benzotriazole.21 It means TEMPO+
may react with 2s or 2v directly by single electron transfer
to form radical cation species of 2s or 2v in our system.
However, both yield of them were significantly lower than
the yield of pyrazole. So, we thought the single-electron ox-
idation was side reaction here, and no single-electron oxi-
dation of substrates was involved in the formation of prod-
ucts.
The ring-opened adduct o-hydroxyamidine had been
proved to be a usual intermediate in the C-H amination of
benzoxazole, especially when using secondary amines as ni-
trogen sources under metal-free conditions.3a,3b,3d However,
the nucleophilicity of pyrazole was too weak to open the cy-
cle of benzoxazole directly. Therefore, on the basis of re-
lated literatures3a,3b ,22 and previous experiments, a possible
mechanism for the transformations was proposed (Scheme
6). Initially, TEMPO+ is generated in the presence of
PhI(OAc)2 or electricity. Then, benzoxazole could be acti-
vated by TEMPO+. The activation by AcOH which could be
generated from PhI(OAc)2 cannot be ruled out else, alt-
hough it did not help when we used it to improve the yields
EXPERIMENTAL SECTION
General Information. Proton nuclear magnetic resonance
(1H-NMR, 600 MHz) and carbon-13 nuclear magnetic reso-
nance (13C-NMR, 150 MHz) spectra were measured on a JNM-
ECZ600R/S1 (JEOL, Tokyo, Japan) with CDCl3 as solvent and
recorded in ppm relative to an internal tetramethylsilane
standard. High resolution mass spectra (HRMS) were recorded
on a 6520 Q-TOF MS system (Agilent, Santa Clara, CA, USA) us-
ing an electrospray (ESI) ionization source. Low resolution
mass spectra were obtained on an Agilent 1260-6120 ESI-
LC/MS. Known compounds were confirmed by 1H-NMR spectra
according to literatures. The instrument for electrolysis is
multi-channel potentiostat (A-BF SS-3305D) (made in China).
The dimension parameter of platinum plate electrode and re-
ticulated vitreous carbon electrode are 10 mm×10 mm×0.1 mm,
and 10 mm × 10 mm × 5 mm. Cyclic voltammetry measure-
ments were performed in dry CH3CN on a CHI 610E electro-
chemical analyzer with a three-electrode cell, using 0.1 M
Bu4NPF6 as supporting electrolyte, AgCl/Ag as reference elec-
trode, platinum disk as working electrode, Pt wire as counter
electrode, and scan rate at 100 mV/s. Unless otherwise noted,
reagents were purchased from Aldrich Chemical Co. (Darm-
stadt, Germany), Adamas-beta (Shanghai, China) and Energy
Chemical (Shanghai, China) and used without further purifica-
tion. Benzoxazole derivatives3f,23 and pyrazole derivatives24 are
prepared according to the literature.
General Procedure for Amination of Benzoxazoles with
N-heterocycles. A glass tube equipped with a magnetic stir bar
charged with benzoxazole derivative (0.5 mmol, 1.0 equiv),
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TEMPO (78 mg, 0.5 mmol, 1.0 equiv), N-heterocycles (2.0
reduced pressure. The resulting residue was purified by col-
umn chromatography to afford the product (59 mg, 58%). The
identity and purity of the product was confirmed 1H-NMR spec-
tra according to literatures.3c
5-methyl-2-(1H-pyrazol-1-yl)benzo[d]oxazole (3b). White
solid (91 mg, 91%); mp 83-85 °C; 1H NMR (600 MHz, CDCl3): δ
8.38 (d, J = 2.7 Hz, 1H), 7.87 (d, J = 1.2 Hz, 1H), 7.47 (s, 1H), 7.44
(d, J = 8.3 Hz, 1H), 7.13 (dd, J = 8.3, 0.9 Hz, 1H), 6.58-6.56 (m,
1H), 2.47 (s, 3H). 13C {1H} NMR (150 MHz, CDCl3): δ 153.8,
147.60, 144.4, 140.9, 135.2, 129.8, 125.8, 119.6, 110.1, 109.6,
21.6; HRMS (ESI): [M+H]+ calcd. for C11H9N3O: m/z = 200.0818;
found, 200.0816.
1
2
3
4
5
6
7
8
equiv), 1,2-dichloroethane (1 ml), then PhI(OAc)2 (322 mg, 1.0
mmol, 2.0 equiv) was added. After stirring of the solution at
room temperature for 48 h under an air atmosphere. The mix-
ture was then diluted with DCM, washed with a saturated solu-
tion of NaHCO3 and the aqueous layer was extracted with DCM.
The combined organic layers were dried over Na2SO4 and con-
centrated under reduced pressure. The resulting residue was
purified by column chromatography. The identity and purity of
the unknown product was confirmed by HRMS, 1H-NMR and
13C-NMR. Known compounds 3a, 3s, and 3v were confirmed by
1H-NMR spectra according to literatures.11
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Electro-Oxidative Amination of Benzoxazole with Pyra-
zole. A solution of benzoxazole (60 mg, 0.5 mmol), pyrazole
(136 mg, 2.0 mmol), TEMPO (156 mg, 1.0 mmol) and Bu4NI
(369 mg, 1.0 mmol) in CH3CN (2 ml) was stirred at 25 °C under
air atmosphere in glass tube which was equipped with plati-
num plate electrodes (1.0 cm×1.0 cm×0.1 mm) as both the an-
ode and cathode. The reaction mixture was stirred and electro-
lyzed at a constant cell potential of 1.2 V for 120 hours. The re-
action mixture was directly concentrated in vacuo, then diluted
with DCM, washed with water and the aqueous layer was ex-
tracted with DCM. The combined organic layers were dried
over Na2SO4 and concentrated under reduced pressure. The
residue was purified by chromatography on silica gel to afford
pure product.
A Large-Scale Synthesis for Amination of Benzoxazole
with Pyrazole. A flame-dried round-bottom flask equipped
with a stir bar was evacuated and filled with nitrogen. The flask
was then charged with benzoxazole (2.38 g, 20.0 mmol, 1.0
equiv), TEMPO (3.12 g, 20.0 mmol, 1.0 equiv), pyrazole (2.72 g,
40.0 mmol, 2.0 equiv), dry 1,2-dichloroethane (50 ml), and
placed in an ice bath. To this solution was added PhI(OAc)2
(12.88 g, 40.0 mmol, 2.0 equiv) with stirring, and was strirred
at 0 °C for 0.5 h. After stirring of the solution at room tempera-
ture for another 48 h. The mixture was then diluted with DCM,
washed with a saturated solution of NaHCO3 and the aqueous
layer was extracted with DCM. The combined organic layers
were dried over Na2SO4 and concentrated under reduced pres-
sure. The resulting residue was purified by column chromatog-
raphy to afford 3a (2.99g, 81%).
Amination of Anisole with Pyrazole. A glass tube equipped
with a magnetic stir bar was evacuated and filled with nitrogen.
The tube was then charged with anisole (54 mg, 0.5 mmol, 1.0
equiv), TEMPO (78 mg, 0.5 mmol, 1.0 equiv), pyrazole (68 mg,
1.0 mmol, 2.0 equiv), 1,2-dichloroethane (1 ml), then NFSI (315
mg, 1.0 mmol, 2.0 equiv) was added at 0 °C. After stirring of the
solution at room temperature for another 48 h. The mixture
was then diluted with DCM, washed with a saturated solution
of NaHCO3 and the aqueous layer was extracted with DCM. The
combined organic layers were dried over Na2SO4 and concen-
trated under reduced pressure. The resulting residue was pu-
rified by column chromatography to afford the product (29 mg,
33%). The identity and purity of the product was confirmed by
1H-NMR spectra according to literatures.12a
Amination of Benzoxazole with Morpholine. A glass tube
equipped with a magnetic stir bar charged with benzoxazole
(60 mg, 0.5 mmol, 1.0 equiv), TEMPO (78 mg, 0.5 mmol, 1.0
equiv), morpholine (87mg, 1.0 mmol, 2.0 equiv), 1,2-dichloro-
ethane (1 ml), then PhI(OAc)2 (322 mg, 1.0 mmol, 2.0 equiv)
was added. After stirring of the solution at room temperature
for 48 h under an air atmosphere. The mixture was then diluted
with DCM, washed with a saturated solution of NaHCO3 and the
aqueous layer was extracted with DCM. The combined organic
layers were dried over Na2SO4 and concentrated under
5-methoxy-2-(1H-pyrazol-1-yl)benzo[d]oxazole (3c). White
solid (100 mg, 93%); mp 82-84 °C; 1H NMR (600 MHz, CDCl3):
δ 8.35 (d, J = 2.7 Hz, 1H), 7.85 (s, 1H), 7.43 (d, J = 8.9 Hz, 1H),
7.16 (d, J = 2.5 Hz, 1H), 6.89 (dd, J = 8.9 Hz, 2.4, 1H), 6.56-6.54
(m, 1H), 3.84 (s, 3H). 13C {1H} NMR (150 MHz, CDCl3): δ (150
MHz, CDCl3) d=158.0, 154.4, 144.5, 144.0, 141.7, 129.8, 112.8,
111.0, 109.7, 103.3, 56.1; HRMS (ESI): [M+H]+ calcd. for
C11H9N3O2: m/z = 216.0768; found, 216.0765.
5-(tert-butyl)-2-(1H-pyrazol-1-yl)benzo[d]oxazole
(3d).
1
White solid (108 mg, 90%); mp 68-70 °C; H NMR (600 MHz,
CDCl3): δ 8.38 (d, J = 2.6 Hz, 1H), 7.87 (s, 1H), 7.70 (s, 1H), 7.48
(d, J = 8.6 Hz, 1H), 7.39 (d, J = 8.8 Hz, 1H), 6.57-6.56 (m, 1H),
1.38 (s, 9H). 13C {1H} NMR (150 MHz, CDCl3): δ 154.0, 149.1,
147.5, 144.5, 140.7, 129.9, 122.5, 116.4, 110.0, 109.7, 35.1, 31.9;
HRMS (ESI): [M+H]+ calcd. for C14H15N3O: m/z = 242.1288;
found, 242.1283.
5-fluoro-2-(1H-pyrazol-1-yl)benzo[d]oxazole (3e). Pale pink
solid (90 mg, 89%); mp 135-137 °C; 1H NMR (600 MHz, CDCl3):
δ 8.36 (d, J = 2.7 Hz, 1H), 7.88 (s, 1H), 7.49 (dd, J = 8.9, 4.2 Hz,
1H), 7.36 (dd, J = 8.2, 2.6 Hz, 1H), 7.05 (td, J = 9.1, 2.5 Hz, 1H),
6.59-6.56 (m, 1H). 13C {1H} NMR (150 MHz, CDCl3): δ 160.6 (d,
J = 241.5 Hz), 155.1, 145.8, 144.9, 141.8 (d, J = 13.3 Hz), 130.1,
112.4 (d, J= 26.1 Hz), 111.2 (d, J = 10.1 Hz), 110.1, 106.6 (d, J=
26.2 Hz); HRMS (ESI): [M+H]+ calcd. for C10H6FN3O: m/z =
204.0568; found, 204.0566.
5-chloro-2-(1H-pyrazol-1-yl)benzo[d]oxazole (3f). White
solid (88 mg, 80%); mp 128-131 °C; 1H NMR (600 MHz, CDCl3):
δ 8.38 (d, J = 2.7 Hz, 1H), 7.90 (s, 1H), 7.67 (d, J = 2.0 Hz, 1H),
7.50 (d, J = 8.7 Hz, 1H), 7.32 (dd, J = 8.6 Hz, 2.1, 1H), 6.60-6.59
(m, 1H). 13C {1H} NMR (150 MHz, CDCl3): δ 154.8, 148.0, 145.0,
142.0, 130.9, 130.1, 125.2, 119.8, 111.6, 110.2; HRMS (ESI):
[M+H]+ calcd. for C10H6ClN3O: m/z
220.0269.
= 220.0272; found,
5-bromo-2-(1H-pyrazol-1-yl)benzo[d]oxazole (3g). Pale pink
solid (113 mg, 86%); mp 130-132 °C; 1H NMR (600 MHz, CDCl3):
δ 8.34 (d, J = 2.7 Hz, 1H), 7.86 (s, 1H), 7.78 (s, 1H), 7.42-7.41 (m,
2H), 6.57-6,55 (m, 1H). 13C {1H} NMR (150 MHz, CDCl3): δ 154.5,
148.4, 145.0, 142.4, 130.1, 127.8, 122.7, 118.1, 112.0, 110.1;
HRMS (ESI): [M+H]+ calcd. for C10H6BrN3O: m/z = 263.9767;
found, 263.9767.
methyl
2-(1H-pyrazol-1-yl)benzo[d]oxazole-5-carboxylate
(3h). white solid (114 mg, 94%); mp 151-153 °C; 1H NMR (600
MHz, CDCl3): δ 8.39 (s, 1H), 8.37-8.33 (m, 1H), 8.11-8.04 (m,
1H), 7.89 (s, 1H), 7.65-7.54 (m, 1H), 6.59 (d, J = 1.3 Hz, 1H), 3.95
(s, 3H). 13C {1H} NMR (150 MHz, CDCl3): δ 166.5, 154.7, 152.4,
145.0, 141.1, 130.2, 128.0, 126.9, 121.6, 110.6, 110.2, 52.5;
HRMS (ESI): [M+H]+ calcd. for C12H9N3O3: m/z = 244.0717;
found, 244.0713.
1-(2-(1H-pyrazol-1-yl)benzo[d]oxazol-7-yl)ethan-1-one (3i).
white solid (103 mg, 91%); mp 152-154 °C; 1H NMR (600 MHz,
CDCl3): δ 8.39 (d, J = 2.7 Hz, 1H), 7.93-7.84 (m, 3H), 7.47-7.41
(m, 1H), 6.60 (dd, J = 2.6 Hz, 1.4, 1H), 2.87 (s, 3H). 13C {1H} NMR
(150 MHz, CDCl3): δ 194.4, 154.3, 148.1, 145.1, 142.1, 130.2,
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 7
125.4, 125.3, 124.6, 122.1, 110.2, 30.4; HRMS (ESI): [M+H]+
δ 161.8, 152.9, 149.6, 144.9, 140.6, 132.9, 125.7, 125.5, 120.1,
118.9, 111.0, 61.1, 14.4; HRMS (ESI): [M+H]+ calcd. for
C13H11N3O3: m/z = 258.0873; found, 258.0871.
1
2
3
4
5
6
7
8
calcd. for C12H9N3O2: m/z = 228.0768; found, 228.0764.
5-phenyl-2-(1H-pyrazol-1-yl)benzo[d]oxazole (3j). white
solid (125 mg, 96%); mp 130-132 °C; 1H NMR (600 MHz, CDCl3):
δ 8.40 (d, J = 2.0 Hz, 1H), 7.88 (d, J = 11.6 Hz, 2H), 7.61 (d, J = 6.9
Hz, 3H), 7.57-7.53 (m, 1H), 7.47 (dd, J = 11.1, 3.9 Hz, 2H), 7.37
(dd, J = 10.9, 4.1 Hz, 1H), 6.58 (d, J = 1.7 Hz, 1H). 13C {1H} NMR
(150 MHz, CDCl3): δ 154.3, 149.0, 144.7, 141.5, 140.9, 139.4,
130.0, 129.0, 127.6, 124.4, 118.2, 110.8, 109.9; HRMS (ESI):
[M+H]+ calcd. for C16H11N3O: m/z = 262.0975; found, 262.0970.
5-nitro-2-(1H-pyrazol-1-yl)benzo[d]oxazole (3k). white solid
(56 mg, 49%); mp 183-185 °C; 1H NMR (600 MHz, CDCl3): δ
8.54 (d, J = 2.0 Hz, 1H), 8.40 (d, J = 2.7 Hz, 1H), 8.29 (dd, J = 8.9,
2.1 Hz, 1H), 7.92 (s, 1H), 7.68 (d, J = 8.9 Hz, 1H), 6.64-6.62 (m,
1H). 13C {1H} NMR (150 MHz, CDCl3): δ 155.9, 152.9, 146.0,
145.6, 141.5, 130.5, 121.0, 115.9, 111.1, 110.7; HRMS (ESI):
[M+H]+ calcd. for C10H6N4O3: m/z = 231.0513; found, 231.0509.
5-(2-(benzo[d]oxazol-5-yl)-1,1,1,3,3,3-hexafluoropropan-2-
yl)-2-(1H-pyrazol-1-yl)benzo[d]oxazole (3l-1). white solid (108
mg, 48%); mp 156-159 °C; 1H NMR (600 MHz, CDCl3): δ 8.37 (d,
J = 2.7 Hz, 1H), 8.15 (s, 1H), 7.96 (s, 1H), 7.89 (s, 1H), 7.81 (s,
1H), 7.57 (t, J = 8.4 Hz, 2H), 7.40 (d, J = 8.8 Hz, 1H), 7.35 (d, J =
8.7 Hz, 1H), 6.59 (dd, J = 2.5 Hz, 1.3, 1H). 13C {1H} NMR (150
MHz, CDCl3): δ 154.8, 153.7, 150.1, 149.5, 145.0, 141.0, 140.2,
131.1, 130.3, 130.2, 128.0, 127.1, 124.3 (d, J = 285.2 Hz), 123.2,
122.1, 110.9, 110.6, 110.2, 65.0 (p, J = 25.2 Hz); HRMS (ESI):
[M+H]+ calcd. for C20H10F6N4O2: m/z = 453.0781; found,
453.0771.
1-(benzo[d]oxazol-2-yl)-1H-pyrazole-4-carbonitrile
(3q).
white solid (44 mg, 42%); mp 188-190 °C; 1H NMR (600 MHz,
CDCl3): δ 8.81 (s, 1H), 8.13 (s, 1H), 7.77-7.71 (m, 1H), 7.64-7.59
(m, 1H), 7.45-7.40 (m, 2H). 13C {1H} NMR (150 MHz, CDCl3): δ
152.1, 149.7, 145.4, 140.3, 134.9, 126.1, 126.0, 120.5, 111.7,
111.2, 97.0; HRMS (ESI): [M+H]+ calcd. for C11H6N4O: m/z =
211.0614; found, 211.0613
2-(1H-1,2,4-triazol-1-yl)benzo[d]oxazole (3t). white solid (47
mg, 50%); mp 127-130 °C; 1H NMR (600 MHz, CDCl3): δ 9.05 (s,
1H), 8.21 (s, 1H), 7.73 (dd, J = 5.3, 1.8 Hz, 1H), 7.60 (dd, J = 5.1,
1.5 Hz, 1H), 7.44-7.37 (m, 2H). 13C {1H} NMR (150 MHz, CDCl3):
δ 154.2, 151.2, 149.5, 144.1, 140.2, 125.9, 125.8, 120.4, 111.1;
HRMS (ESI): [M+H]+ calcd. for C9H6N4O: m/z = 187.0614; found,
187.0612
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
2-(1H-1,2,3-triazol-1-yl)benzo[d]oxazole, 2-(2H-1,2,3-triazol-
2-yl)benzo[d]oxazole (3u). white solid (60 mg, 64%); mp 84-
1
88 °C; H NMR (600 MHz, CDCl3): δ 8.49 (d, J = 1.1 Hz, 0.86H),
8.03 (s, 2 H), 7.90 (s, 0.86H), 7.79-7.75 (m, 1.86H), 7.65-7.61 (m,
1.86H), 7.44-7.40 (m, 3.72H). 13C {1H} NMR (150 MHz, CDCl3):
δ 152.6, 151.4, 149.7, 149.6, 140.6, 140.1, 138.7, 134.6, 126.2,
126.2, 125.9, 125.9, 125.8, 123.5, 120.7, 120.5, 111.3, 111.1;
HRMS (ESI): [M+H]+ calcd. for C9H6N4O: m/z = 187.0614; found,
187.0612
ASSOCIATED CONTENT
5,5'-(perfluoropropane-2,2-diyl)bis(2-(1H-pyrazol-1-
Supporting Information
yl)benzo-[d]oxazole) (3l-2).white solid (163 mg, 63%); mp 195-
1
The Supporting Information is available free of charge on the
ACS Publications website.
197 °C; H NMR (600 MHz, CDCl3): δ 8.38 (d, J = 2.7, 2H), 7.90
(d, J = 1.1, 2H), 7.83 (s, 2H), 7.57 (d, J = 8.8, 2H), 7.35 (d, J = 8.7,
2H), 6.61-6.57 (m, 2H). 13C {1H} NMR (150 MHz, CDCl3): δ 154.8,
149.5, 145.1, 141.0, 131.0, 130.2, 127.1, 124.3 (d, J = 285.3 Hz),
122.1, 110.6, 110.4, 65.0 (p, J = 25.7 Hz); HRMS (ESI): [M+H]+
calcd. for C23H12F6N6O2: m/z = 519.0999; found, 519.0987.
2-(3-methyl-1H-pyrazol-1-yl)benzo[d]oxazole (3m). white
solid (55 mg, 55%); mp 100-102 °C; the regioselectivity is sup-
ported by an X-ray crystallographic structure determination,
see Supporting Information; 1H NMR (600 MHz, CDCl3): δ 8.25
(d, J = 2.6 Hz, 1H), 7.64 (d, J = 7.4 Hz, 1H), 7.54 (d, J = 7.9 Hz, 1H),
7.33 (t, J = 7.4 Hz, 1H), 7.29 (td, J = 7.9, 1.1 Hz, 1H), 6.35 (d, J =
2.7 Hz, 1H), 2.42 (s, 3H). 13C {1H} NMR (150 MHz, CDCl3): δ
154.6, 153.9, 149.4, 141.0, 130.5, 125.3, 124.6, 119.5, 110.7,
110.3, 13.9; HRMS (ESI): [M+H]+ calcd. for C11H9N3O: m/z =
200.0818; found, 200.0816.
2-(4-chloro-1H-pyrazol-1-yl)benzo[d]oxazole (3n). white
solid (70 mg, 64%); mp 116-118 °C; 1H NMR (600 MHz, CDCl3):
δ 8.36 (d, J = 0.4 Hz, 1H), 7.80 (s, 1H), 7.70-7.67 (m, 1H), 7.57
(dd, J = 7.4, 1.5 Hz, 1H), 7.40-7.34 (m, 2H). 13C {1H} NMR (150
MHz, CDCl3): δ 153.0, 149.5, 143.3, 140.6, 127.4, 125.6, 125.2,
119.9, 115.1, 110.9; HRMS (ESI): [M+H]+ calcd. for C10H6ClN3O:
m/z = 220.0272; found, 220.0271.
2-(4-bromo-1H-pyrazol-1-yl)benzo[d]oxazole (3o). white
solid (85 mg, 65%); mp 115-117 °C; 1H NMR (600 MHz, CDCl3):
δ 8.40 (d, J = 2.6 Hz, 1H), 7.82 (d, J = 2.2 Hz, 1H), 7.68 (dd, J = 7.2,
1.4 Hz, 1H), 7.60-7.53 (m, 1H), 7.41-7.32 (m, 2H). 13C {1H} NMR
(150 MHz, CDCl3) δ: 152.9, 149.5, 145.2, 140.7, 129.7, 125.6,
125.3, 120.0, 110.9, 98.6; HRMS (ESI): [M+H]+ calcd. for
C10H6BrN3O: m/z = 263.9767; found, 263.9766.
ethyl 1-(benzo[d]oxazol-2-yl)-1H-pyrazole-4-carboxylate (3p).
white solid (95 mg, 74%); mp 132-135 °C; 1H NMR (600 MHz,
CDCl3): δ 8.84 (d, J = 1.2 Hz, 1H), 8.21 (s, 1H), 7.70 (d, J = 7.2 Hz,
1H), 7.57 (d, J = 7.8 Hz, 1H), 7.39-7.36 (m, 2H), 4.35 (q, J = 7.2
Hz, 2H), 1.37 (t, J = 7.2 Hz, 3H). 13C {1H} NMR (150 MHz, CDCl3):
Experimental details, analytical data, mass spectrum, cyclic
voltammogram, and NMR spectra (PDF)
AUTHOR INFORMATION
Corresponding Author
* E-mail: lqchem@163.com (Q. Liu); xqyu@scu.edu.cn (X.-
Q.Y.).
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
Financial support for this research from Start-up Fund of
Chengdu University (No. 2081918024), Sichuan Science Tech-
nology Program (No. 2018JY0222) and China Scholarship
Council (No. 201808510023) is gratefully acknowledged.
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