Metal-free synthesis of triarylated (: Z)-nitrones via H2O-mediated 1,3-dipolar transfer under aerobic conditions

Article abstract of DOI:10.1039/c8gc03593h

A new and environmentally benign protocol aimed at the generation of triarylated (Z)-nitrones in generally good yields has been developed via metal- and catalyst-free H₂O-mediated 1,3-dipolar transfer reaction of para-quinone methides (p-QMs) with diarylated nitrones under aerobic conditions. The purification of these products only needs to be recrystallized by a mixed solvent comprising small amounts of petroleum ether and ethyl acetate, thereby avoiding the requirement of traditional chromatography. This new 1,3-dipolar strategy features broader substrate scope, green process, and mild conditions.

Full text of DOI:10.1039/c8gc03593h

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DOI: 10.1039/C8GC03593H
Journal Name
ARTICLE
Metal-free synthesis of triarylated (Z)-nitrones via H O-mediated
2
1
,3-dipolar transfer under aerobic conditions
Received 00th January 20xx,
Accepted 00th January 20xx
a
a
,a
,a
Ke Chen, Wen-Juan Hao, Shu-Jiang Tu,* and Bo Jiang*
DOI: 10.1039/x0xx00000x
A new and environmentally benign protocol aimed at the generation of triarylated (Z)-nitrones in generally good yields has
been developed via metal- and catalyst-free H O-mediated 1,3-dipolar transfer reaction of para-quinone methides (p-
2
www.rsc.org/
QMs) with diarylated nitrones under aerobic conditions. The purification of these products only needs to be recrystallized
by the mixed solvent of small amount of petroleum ether and ethyl acetate, thereby avoiding traditional chromatography.
The current new 1,3-dipolar strategy features broader substrate scope, green process and mild conditions.
access nitrogen-containing heterocycles.7-9 Consequently,
substantial efforts have been contributed to establish reliable
methods for the preparation of nitrones, including N-alkylation
Introduction
The research for an efficient and practical synthetic strategy
toward valuable target molecules, with simultaneous
consideration of the economic and environmental aspects, is
one of the most significant goals in both academia and
1
0
11
of
oximes,
oxidation
of
secondary
amines,
1
2
13
hydroxylamines, or imines, and condensation between
carbonyls with N-substituted hydroxylamine as well as zinc-
1
4
mediated reduction coupling between aldehydes and
1
industry. Due to organic solvents are generally thought to be
1
5
nitrobenzenes. Most of these approaches lead to the
formation of disubstituted nitrones while the investigation on
the preparation of trisubstituted nitrones, especially
the highest contributors toward environmental waste, water
as a safe and eco-friendly solvent proved to be a highly
attractive and sustainable choice without percolating
hazardous organic solvents to the environment during the
reaction process. On the other hand, numerous fine chemicals
and pharmaceutically active ingredients are typically allowed
1
6
triarylated analogues, were quite less. Due to triarylated
nitrones enable cycloadditions to easily access target cyclic
2
1
7
structures with bis-benzylic quaternary stereocenters, Wang,
Hu and co-workers recently developed a metal-free coupling of
N-nosylhydrazones with nitrosoarenes to synthesize such
molecules, but this protocol demanded NaH as a base
promoter and suffered from poor stereoselectivity with the
3
in low levels of the heavy metal content. Consequently,
metal-free organic transformations are generally believed to
be an utmost prior alternative since such transformations
could avoid the blend of heavy metal into these target
1
8
use of unsymmetrical diarylated hydrazones (Scheme 1a).
4
compounds. It has become clear that the development of new
Therefore, the development of a green and mild synthetic
strategy for the stereoselective synthesis of triarylated
nitrones from readily available substrates is still highly
metal-free
chemical
transformations
following
the
combination of water as an environmentally compatible
solvent to facilitate the preparation of significant molecules
continues to be of great interest in pharmaceutical sciences
and drug discovery.5
Meanwhile, nitrones are a kind of competent 1,3-dipoles
endowed with both nucleophilic and electrophilic sites, serving
as three-atom building units for many important targets of
desirable.
previous work
Ar'
Ph
O
NNHTs
Ph
NO NaH (1.5 equiv)
N
(a)
CH Cl , N , 40 oC
Ar
2
2
2
Ph
Ph
this work
HO
tBu
6
R1
chemical and biomedical potentials. In particular, nitrones can
tBu
be used as applicable 1,3-dipoles in various cycloadditions to
tBu
Ar H2O, 80 o
C
Ar
Ph
N
(b)
HO
O
N
O2 (1.0 atm)
O
R1
O
tBu
1
2
O
H
R1
a. School of Chemistry & Materials Science, Jiangsu Key Laboratory of Green
Synthetic Chemistry for Functional Materials, Jiangsu Normal University, Xuzhou
tBu
3
2
21116, P. R. China. Email: jiangchem@jsnu.edu.cn (BJ); laotu@jsnu.edu.cn (SJT);
H O
, 80 o
OH
2
C
(c)
Fax: +8651683500065; Tel: +8651683500065
O
tBu
†
Footnotes relating to the title and/or authors should appear here.
O
N
R2
Electronic Supplementary Information (ESI) available. CCDC 1879547 (3a) [details
of any supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
Ph
4
Scheme 1. Synthesis of triarylated nitrones
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J. Name., 2013, 00, 1-3 | 1
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Over the years, para-quinone methides (p-QMs) are a class of any Lewis acid, the current transformation could also give a
View Article Online
DOI: 10.1039/C8GC03593H
versatile precursors in the construction of oxygen-containing 70% yield of product 3a (entry 15). Next, our endeavors aimed
molecules.19 Very recently, we have reported Ag/Brønsted acid at improving the formation of 3a were paid by adjusting other
co-catalyzed double cycloaddition of p-QMs with β-alkynyl reaction parameters. The reaction efficiency was found to
ketones for synthesizing functionalized 6,6-benzannulated have an important temperature dependence. A relatively
spiroketals.1 To continue our efforts in this project, we lower conversion was obtained when the reaction
9a
o
reasoned that [4 + 3] cycloaddition of p-QMs 1 with nitrones 2 temperature was changed to either 70 or 90 C (entries 16-17).
could
generate
new
functionalized
benzo[e][1,4,2] In addition, an attempt to conduct the transformation under
dioxazepines 4 (Scheme 1c). Surprisingly, the reaction directed oxygen conditions proved to display a positive impact on the
an unexpected pathway to form triarylated (Z)-nitrones 3 with reaction yield as the product 3a was provided in a higher yield
high regio- and stereoselectivity via 1,3-dipolar transfer of 74% (entry 18). In contract, the reaction under Ar conditions
(
Scheme 1b). Herein, we report this H
transfer reaction, in which H O played dual roles as a reaction results suggest that oxygen plays a key role in the success of
mediator as well as reaction media. Notably, pure triarylated this transformation, which may act as an oxidant. Without
Z)-nitrones were readily isolated by recrystallizing the crude O, the reaction only gave a trace amount of product 3a,
2
O-promoted 1,3-dipolar seriously inhibited the generation of 3a (entry 19). These
2
(
H
2
products with the mixed solvent of petroleum ether and ethyl indicating that H
acetate, thereby avoiding traditional column chromatography 20).
while significantly saving silica gels, solvents and manpower.
2
O could facilitate the transformation (entry
a
Table 1. Optimization of the reaction conditions
Thus, this transformation follows the concept of group-
O
HO
tBu
tBu
tBu
2
0
assisted purification (GAP) chemistry. To the best of our
knowledge, the present 1,3-dipolar transfer protocol first
represents a green and stereoselective synthesis of triarylated
tBu
Cat.
Ph
+
Ph
Ph
N
O
solvent, t
N
(Z)-nitrones that belong to a family of important building
O
OH
O
H
blocks for organic synthesis and drug design.
2a
1a
3a
o
Yield (%)b
Entry
Cat. (10 mol %)
Solvent
t ( C)
Results and discussion
Our initial trial began with the reaction of p-QM 1a and nitrone
1
2
3
Sc(OTf)
Sc(OTf)
Sc(OTf)
3
3
3
toluene
DCE
80
80
80
28
26
MeCN
trace
2
a in the presence of Sc(OTf)
3
(10 mol %) as a Lewis acid in
o
4
5
6
7
8d
9e
1
1
1
1
1
1
16
17
18f
19g
2
Sc(OTf)3
EtOH
THF
1,4-dioxane
80
80
80
80
80
80
80
80
80
80
80
80
90
70
80
80
80
trace
N.R.c
N.R.
67
46
38
68
56
52
70
60
70
58
54
74
<10
trace
toluene at 80 C, the desired product 3a was generated in 28%
yield (Table 1, entry 1). With this preliminary result in hand,
further optimization of the reaction conditions including
solvents, catalysts and reaction temperatures was
subsequently implemented. A variety of reaction media, such
Sc(OTf)
Sc(OTf)
Sc(OTf)
Sc(OTf)
Sc(OTf)
3
3
3
3
3
2
H O
2
H O
2
H O
2
H O
2
H O
2
H O
2
H O
2
H O
2
H O
as 1,2-dichloroethane (DCE), acetonitrile (CH
tetrahydrofuran (THF), 1,4-dioxane, and O, was then
screened for this 1,3-dipolar transfer cascade by employing
Sc(OTf) as the catalyst. The use of DCE led to a slightly lower
yield of product 3a as compared with toluene (entry 1 vs entry
). Exchanging other four organic solvents including CH CN,
3
CN), EtOH,
0
1
2
3
4
5
Cu(OTf)
FeCl ·6H
Ni(ClO
Co(ClO
2
H
2
3
2
O
4
)
2
·6H
·6H
·6H
2
O
3
4
)
)
2
2
O
Co(NO
3
2
2
O
2
3
-
-
-
-
-
-
EtOH, THF, and 1,4-dioxane for DCE all completely suppressed
the generation of 3a (entries 3-6). To our delight, the yield of
H O
2
H O
2
3
a was increased to 67% when H
2
O was selected as the
H
H
-
2
O
O
reaction solvent (entry 7). Subsequently, the phase transfer
catalysts (PTCs) such as tetrabutylammonium bromide (TBAB)
and tetrabutylammonium iodide (TBAI) were employed to
further improve the yield of 3a due to the relatively low
solubility of nitrone in water. Unfortunately, both PTCs were
not beneficial for this transformation and resulted in a
remarkably reduced yield of 3a (entries 8-9). The following
screening of several other common Lewis acids, including
2
0
a
Reaction conditions: 1a (0.10 mmol), 2a (0.20 mmol), catalyst (10 mol
b
%
), solvent (2.0 mL), under air condition. Isolated yield of product 3a
c
d
e
based on 1a. No Reaction (N.R.). Use of TBAB (10 mol %). Use of TBAI
f
g
2
(10 mol %). Under O conditions. Under Ar conditions.
With the optimized conditions established, we set out to
explore the generality of this 1,3-dipole transfer reaction by
examining a variety of p-QM and nitrone components. As
shown in Scheme 2, p-QM 1a was first selected to evaluate the
influence of substituents in the aromatic ring directly bound to
the N-atom of nitrones. As anticipated, all these
transformations completely oriented the stereoselectivity to
Cu(OTf)2, FeCl
Co(NO ·6H O. (entry 10-14) indicated that all of these Lewis
acids could promote the conversion into product 3a, in which
Cu(OTf) and Co(ClO ·6H showed good catalytic
performance in the conversion of 1a into 3a, which is similar to
Sc(OTf) (entries 10 and 14 vs entry 7) Surprisingly, without
3 2 4 2 2 4 2 2
·6H O, Ni(ClO ) ·6H O, Co(ClO ) ·6H O, and
)
3 2
2
2
)
4 2
2
O
3
.
2
| J. Name., 2012, 00, 1-3
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ARTICLE
the generation of the expected triarylated (Z)-nitrones 3b-3j in To demonstrate the synthetic potential of this method, several
View Article Online
DOI: 10.1039/C8GC03593H
4
3
1%-75% yields. Both electron-donating (methyl 2b-2d and transformations were carried out. As shown in Scheme 3, Et N-
ethyl 2e) and electron-withdrawing (fluoro 2f, chloro 2g-2i and promoted [3 + 2] cycloaddition of nitrone 3a with dimethyl
bromo 2j) groups located at different positions of the phenyl acetylenedicarboxylate proceeded successfully to access
ring could tolerate this reaction system well. Functional groups dimethyl 2,3-dihydroisoxazole-4,5-dicarboxylate 5a with bis-
at para-position relative to the N-atom seemed to improve the benzylic quaternary stereocenters in 86% yield. Then, the
efficiency of the reaction, as the corresponding products 3b treatment of nitrone 3a with diphenylpropynone provided
and 3g could be produced in slightly higher yields than those at multi-substituted 2,3-dihydroisoxazole 6a in 53% yield. These
the meta-position (3b vs 3c and 3g vs 3h). Next, p-QMs 1 transformations provide facile strategies for the construction
bearing methyl, t-butyl, methoxy, fluoro, chloro and bromo of dihydroisoxazole skeleton with one tetrasubstituted carbon
groups at different positions in the phenol ring could stereocenter. The structures of products 3, 5a and 6a have
2
participate successfully in this metal-free H O-mediated 1,3- been characterized by their NMR and HRMS analysis.
dipolar transfer reaction, enabling the direct assembly of the Furthermore, in the case of 3a, its structure was based on X-
sole stereoisomeric triarylated (Z)-nitrones 3k−3dd in ray diffraction analysis (Figure 1, see the Supporting
4
2%−89% yields. Among them, p-QM with chloride group Information).
HO
residing in the 4-position of phenol ring was found to show the
high reactivity when reacting with nitrone 2a, furnishing the
corresponding product 3v in 89% yield. However, the presence
of tert-butyl group at 5-postion seems reluctant to undergo
the reaction process as the rather lower conversion into 3l was
observed (42% yield). Notably, the sterically more demanding
C6 methoxy group would be accommodated in this
transformation, furnishing triarylated (Z)-nitrone 3dd in 42%
yield.
tBu
tBu
tBu
HO
Ph
O
N
CO2Me
CO2Me
CO2Me
Ph
N
O
Et3N, CH3CN
+
0 o
CO Me
8
C
tBu
2
OH
O
H
3a
5a (86%)
HO
tBu
tBu
tBu
Ph
O
N
O
Ph
Ph
Et3N, CH3CN HO
Ph
N
O
+
00 o
COPh
OH
1
C
tBu
O
HO
tBu
tBu
tBu
Ph
tBu
O
H
3a
6a (53%)
Ar
H2O, 80 o
O2
C
Ar
Scheme 3. Transformations of product 3a
+
Ph
N
O
N
R1
R1
O
OH
O H
3
OH
1
2
H
N
EtOH
rt
Ph
Ph
+
PhCHO
(a)
Ph
OH
Ph
N
O
Ph
N
3
a, Ar = Ph (74%)
3b, Ar = p-Tolyl (75%)
3c
HO
tBu
HO
tBu
HO
OH
tBu
tBu
,
Ar = m-Tolyl (64%)
d, Ar = 3,4-Me2C6H3 (58%)
Ar 3e, Ar = 4-EtC6H4 (62%)
tBu
tBu
2a (70%)
Not observed
3
Ph
N
O
Ph
N
O
tBu
HO
N
O
tBu
3
3
3
3
3
f, Ar = 4-FC6H4 (41%)
g, Ar = 4-ClC6H4 (67%)
h, Ar = 3-ClC6H4 (61%)
i, Ar = 3,4-Cl2C6H3 (68%)
j, Ar = 3-BrC6H4 (53%)
Me
O
tBu
tBu
tBu
O
H
O
H
O
H
3a-3k
H O, 80 oC
2
3k (60%)
3l (42%)
H
Ph
N
O
N
(b)
+
Ph
OH
O2
HO
HO
HO
tBu
tBu
HO
tBu
tBu
tBu
tBu
tBu
tBu
OH
O H
Ph
3a (31%)
Ph
Ar
1a
Ph
Cl
N
MeO
N
F
N
Br
N
O
O
O
O
H O, 80 oC
N
Ph
N
O
H
Ph
H
O
H
O
H
O
3p-3r
H
2
Ph
N
O
Ph
N
(c)
(d)
PhCHO
+
3
m (55%)
3n (62%)
3o (64%)
O2
Ph
OH
O
3
p, Ar = Ph (69%)
HO
HO
HO
tBu
tBu
tBu
3q, Ar = 4-EtC6H4 (68%)
3r, Ar = 3-BrC6H4 (54%)
2a
8%
7
(4%)
Not observed
tBu
tBu
tBu
H
N
H2O, 80 o
O2
Ph
N
O
Ph
Ph
C
1a
+
+
OH
PhCHO
3a (61%)
N
N
Ph
O
O
Me
O
H
MeO
F
O
H
O
H
Scheme 4. Control experiments
3
s (73%)
3t (51%)
3u (87%)
HO
tBu
HO
HO
tBu
To gain a mechanistic insight into the generation of products 3,
several control experiments were conducted. Due to α-amino
alcohol A may behave as an intermediate for the formation of
products 3, we attempted to prepare this compound by
treatment of N-phenylhydroxylamine with benzaldehyde in
EtOH at room temperature. Unfortunately, the reaction only
tBu
tBu
tBu
3v, Ar = Ph (89%)
tBu
3
3
3
w, Ar = p-Tolyl (82%)
x, Ar = m-Tolyl (81%)
y, Ar = 4-EtC6H4 (73%)
Ph
N
O
Ar
Ph
N
O
N
O
3z, Ar = 3-ClC6H4 (85%)
3aa, Ar = 3,4-Cl2C6H3 (72%) Br
bb, Ar = 3-BrC6H4 (52%)
O
H
Cl
O
H
O
H
OMe
3
3cc (56%)
3dd (49%)
3
v-3bb
2
1
Scheme 2. Substrate scope for forming triarylated (Z)-nitrones
provided nitrone 2a in 70% yield without observation of α-
amino alcohol A (Scheme 4a). The reason for this may be that
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ARTICLE
Journal Name
the α-amino alcohol is very unstable, which easily undergoes
dehydration to give nitrones. Subsequently, N-
phenylhydroxylamine was subjected to the reaction of p-QM
a in 2:1 mole ratio under the standard conditions and the
desired product 3a was provided in 31% yield, indicating N-
phenylhydroxylamine may also be a reaction intermediate
Conclusions
View Article Online
DOI: 10.1039/C8GC03593H
In summary, starting from easily available p-QMs and simple
nitrones, we have established a metal-free H O-mediated 1,3-
dipolar transfer strategy to effectively synthesize triarylated
Z)-nitrones with high stereoselectivity and generally good
2
1
(
yields. Interestingly, water plays dual roles as a mediator as
well as a green solvent, and oxygen as a green oxidant. This
new reaction features environmental friendliness, being
simple to perform, occurring under mild conditions and high
functional tolerance. Further application of these resulting
nitrones is underway in our laboratory.
(Scheme 4b). Next, in absence of p-QM 1a, the reaction of
nitrone 2a was carried out under the standard conditions. The
reaction almost did not work and only 8% yield of
benzaldehyde and 4% yield of diazene 1-oxide 7 was obtained
without observation of N-phenylhydroxylamine (Scheme 4c),
showing that N-phenylhydroxylamine is not an intermediate in
the reaction process. Interestingly, when 2.0 equivalents of
benzaldehyde were added into the reaction system of p-QM
Experiment
1
a and N-phenylhydroxylamine, the yield of product 3a was
General Information
remarkably increased to 61% yield (Scheme 4d). These results
support α-amino alcohol A is a reaction intermediate in the
current transformation.
All one-pot reactions were carried out in a 10-mL reaction tube
equipped with a magnetic stir bar under the O
melting points are uncorrected. The NMR spectra were recorded in
CDCl (or DMSO-d ) on a 400 MHz instrument with TMS as internal
2
conditions. All
3
6
standard. Chemical shifts (δ) were reported in ppm with respect to
TMS. Data are represented as follows: chemical shift, multiplicity (s
=
singlet, d = doublet, t = triplet, m = multiples), coupling constant
(J, Hz) and integration. HRMS analyses were carried out using a
TOF-MS instrument with an ESI source.
General procedure for the synthesis of products 3
Example for the synthesis of 3a. Under the oxygen (1.0 atm)
Figure 1. X-Ray structure of 3a
conditions, 2,6-di-tert-butyl-4-(2-hydroxybenzylidene) cyclohexa-
2
,5-dienone (1a, 0.2 mmol, 62.0 mg), (Z)-N-benzylideneaniline oxide
OH
O
tBu
OH
tBu
OH
tBu
OH
tBu
(2a, 0.4 mmol, 78.8 mg) were added in a 10-mL Schlenk tube. Then,
OH
R2 H2O
R2
1
P.T.
H
2
O (2.0 mL) was added into this reaction system. The reaction vial
Ph
N
O
Ph
N
1
,6-addition
OH
2
o
2
R1
N
R
was sealed and heated at 80 C for 12 hours until TLC (petroleum
ether: ethyl acetate= 5:1) revealed that conversion of the starting
material 1a was completed. The reaction mixture was extracted
with EtOAc and concentrated by vacuum distillation and was
purified by recrystallization with the mixed solvent petroleum
ether/ethyl acetate (about 3.0 ml) to afford the pure product 3a as
pale yellow solid.
OH
N
R
R1
2
A
O
Ph
HO
B
Ph
C
OH
HO
tBu
OH
tBu
OH
tBu
tBu
O2
R2
N
O
N
R1
R2
H2O
R1
PhCHO
O
H
D
3
(
Z)-N-((3,5-di-tert-butyl-4-hydroxyphenyl)(2-hydroxyphenyl)
methylene)aniline oxide (3a)
On the basis of the above results, a reasonable mechanism for Pale yellow solid, 62 mg, 74%; mp 221-222 C; H NMR (400 MHz,
this reaction was proposed as shown in Scheme 5. At first, CDCl ; δ, ppm) 11.13 (s, 1H), 7.53-7.49 (m, 1H), 7.34-7.29 (m, 4H),
nucleophilic addition of H
O into nitrones 2 generates unstable 7.28-7.27 (m, 1H), 7.19-7.17 (m, 1H), 7.05-7.03 (m, 1H), 6.90 (s, 2H),
intermediate A, which is
reversible process. When 6.87-6.83 (m, 1H), 5.46 (s, 1H), 1.25 (s, 18H). 13C NMR (100 MHz,
electrophilic p-QMs 1 exist in the reaction system, a fast 1,6- CDCl ; δ, ppm) 160.9, 157.6, 155.3, 147.3, 135.8, 133.9, 133.8,
Scheme 5 Proposed mechanisms for forming products 3
o
1
3
2
a
3
addition of N-atom from α-amino alcohol A into p-QMs 1
occurs, providing intermediate B, followed by proton transfer
1
29.4, 128.8, 128.6, 125.6, 124.9, 122.0, 120.9, 118.9, 34.2, 30.0. IR
-1
(KBr, ν, cm ) 3481, 3415, 2955, 1601, 1507, 1437, 1235, 1114, 768.
(
P.T.) and the release of benzaldehyde to give intermediate D.
Finally, intermediate D is converted into products 3 through
the oxidization in the presence of O
-
HRMS (ESI) m/z: [M-H] Calcd for C27
H30NO
3
416.2226; Found
4
(
16.2208.
Z)-N-((3,5-di-tert-butyl-4-hydroxyphenyl)(2-
hydroxyphenyl)methylene)-4-methylaniline oxide (3b)
2
.
4
| J. Name., 2012, 00, 1-3
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Page 5 of 10
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Journal Name
ARTICLE
o
1
o
1
Pale yellow solid, 65 mg, 75%; mp 224-225 C; H NMR (400 MHz, Yellow solid, 60 mg, 67%; mp 246-247 C; H NMR (400 MHz, CDCl ;
3
View Article Online
CDCl
3
; δ, ppm) 7.52-7.48 (m, 1H), 7.20-7.17 (m, 3H), 7.07 (d, J = 8.4 δ, ppm) 7.54-7.50 (m, 1H), 7.26 (s, 4H), 7.19D-O7.I1: 170(.1m0,391/HC)8,G7C.0053-579.30H2
Hz, 2H), 7.05-7.03 (m, 1H), 6.89 (s, 2H), 6.86-6.82 (m, 1H), 5.46 (s, (m, 1H), 6.89-6.84 (m, 3H), 5.53 (s, 1H), 1.27 (s, 18H). 13C NMR (100
1
1
1
3
H), 2.32 (s, 3H), 1.25 (s, 18H). 13C NMR (100 MHz, CDCl
60.8, 157.4, 155.2, 144.9, 138.8, 135.8, 133.9, 133.7, 129.4, 129.2, 133.9, 129.4, 128.8, 126.3, 125.4, 121.7, 121.0, 119.0, 34.3, 30.0. IR
25.8, 124.7, 122.0, 120.9, 118.8, 34.2, 30.0, 21.0. IR (KBr, ν, cm ) (KBr, ν, cm ) IR (KBr, ν, cm ) 3551, 3425, 2965, 1600, 1507, 1437,
3 3
; δ, ppm) MHz, CDCl ; δ, ppm) 160.9, 158.0, 155.6, 145.8, 136.1, 134.4, 134.0,
-1
-1
-1
-
550, 3421, 2953, 1599, 1510, 1437, 1234, 1119, 768. HRMS (ESI) 1234, 1118, 771. HRMS (ESI) m/z: [M-H] Calcd for C27
H39ClNO
3
-
m/z: [M-H] Calcd for C28
H32NO
3
430.2382; Found 430.2368.
450.1836; Found 450.1840.
(
Z)-N-((3,5-di-tert-butyl-4-hydroxyphenyl)(2-
(Z)-3-chloro-N-((3,5-di-tert-butyl-4-hydroxyphenyl)(2-
hydroxyphenyl)methylene)aniline oxide (3h)
Yellow solid, 55 mg, 61%; mp 183-184 C; H NMR (400 MHz, CDCl ;
3
hydroxyphenyl)methylene)-3-methylaniline oxide (3c)
o
1
o
1
Yellow solid, 55 mg, 64%; mp 178-179 C; H NMR (400 MHz, CDCl
δ, ppm) 7.53-7.48 (m, 1H), 7.19-7.12 (m, 3H), 7.09-7.05 (m 3H), 6.90 δ, ppm) 7.55-7.51 (m, 1H), 7.33-7.29 (m, 1H), 7.26-7.16 (m, 4H),
s, 2H), 6.87-6.83 (m, 1H), 5.47 (s, 1H), 2.25 (s, 3H), 1.25 (s, 18H). 13
7.07-7.05 (m, 1H), 6.90 (s, 2H), 6.89-6.85 (m, 1H), 5.53 (s, 1H), 1.28
NMR (100 MHz, CDCl ; δ, ppm) 160.9, 158.3, 155.6,
; δ, ppm) 160.8, 157.5, 155.2, 147.2, 138.9, (s, 18H). 13C NMR (100 MHz, CDCl
35.8, 133.9, 133.7, 129.2, 128.6, 125.8, 125.6, 121.9, 121.9, 120.9, 148.1, 136.2, 134.4, 134.1, 134.0, 129.8, 129.3, 128.7, 125.6, 125.3,
3
;
(
C
3
3
1
1
1
C
-1
-1
18.8, 34.2, 30.0, 21.0. IR (KBr, ν, cm ) 3541, 3426, 2968, 1598, 123.1, 121.6, 121.0, 119.0, 34.3, 30.0. IR (KBr, ν, cm ) 3566, 3419,
508, 1438, 1238, 1120, 795. HRMS (ESI) m/z: [M-H] Calcd for 2958, 1558, 1509, 1439, 1236, 1112, 683. HRMS (ESI) m/z: [M-H]-
-
28
H
32NO
3
430.2382; Found 430.2385.
3
Calcd for C27H29ClNO 450.1836; Found 450.1850.
(
Z)-N-((3,5-di-tert-butyl-4-hydroxyphenyl)(2-
(Z)-3,4-dichloro-N-((3,5-di-tert-butyl-4-hydroxyphenyl)(2-
hydroxyphenyl)methylene)aniline oxide (3i)
Yellow solid, 66 mg, 68%; mp 205-206 C; H NMR (400 MHz, CDCl ;
3
hydroxyphenyl)methylene)-3,4-dimethylaniline oxide (3d)
o
1
o
1
Yellow solid, 52 mg, 58%; mp 178-179 C; H NMR (400 MHz, CDCl
δ, ppm) 7.52-7.48 (m, 1H), 7.19-7.17 (m, 1H), 7.07-7.05 (m, 2H), δ, ppm) 10.89 (s, 1H), 7.56-7.52 (m, 1H), 7.40 (d, J = 2.4 Hz, 1H),
.00-6.97 (m, 2H), 6.89 (s, 2H), 6.86-6.82 (m, 1H), 5.45 (s, 1H), 2.21 7.37 (d, J = 8.8 Hz, 1H), 7.20-7.14 (m, 2H), 7.07-7.05 (m, 1H), 6.90-
s, 3H), 2.15 (s, 3H), 1.25 (s, 18H). 13C NMR (100 MHz, CDCl ; δ, 6.85 (m, 3H), 5.56 (s, 1H), 1.29 (s, 18H). 13C NMR (100 MHz, CDCl
ppm) 160.8, 157.4, 155.2, 145.0, 137.4, 137.1, 135.7, 133.8, 133.6, δ, ppm) 161.0, 158.6, 155.9, 146.2, 136.4, 134.3, 134.0, 132.8,
3
;
7
(
3
3
;
1
1
1
4
29.6, 129.2, 126.0, 125.9, 122.1, 121.9, 120.9, 118.8, 34.2, 30.0, 132.7, 130.2, 129.2, 127.3, 125.2, 124.2, 121.4, 121.1, 119.2, 34.3,
-1
-1
9.5, 19.4. IR (KBr, ν, cm ) 3554, 3450, 2959, 1574, 1512, 1437, 30.0. IR (KBr, ν, cm ) 3567, 3418, 2970, 1599, 1506, 1438, 1233,
-
-
234, 1108, 827. HRMS (ESI) m/z: [M-H] Calcd for C29
H
34NO
3
1120, 772. HRMS (ESI) m/z: [M-H] Calcd for C27
H28Cl
2
NO
3
484.1446;
44.2539; Found 444.2567.
Found 484.1430.
(
Z)-N-((3,5-di-tert-butyl-4-hydroxyphenyl)(2-hydroxyphenyl)
methylene)-4-ethylaniline oxide (3e)
(Z)-3-bromo-N-((3,5-di-tert-butyl-4-hydroxyphenyl)(2-
hydroxyphenyl)methylene)aniline oxide (3j)
Yellow solid, 52 mg, 53%; mp 184-185 C; H NMR (400 MHz, CDCl ;
3
o
1
o
1
Yellow solid, 55 mg, 62%; mp 237-238 C; H NMR (400 MHz, CDCl
3
;
δ, ppm) 7.52-7.48 (m, 1H), 7.24-7.20 (m, 2H), 7.18-7.16 (m, 1H), δ, ppm) 10.99 (s, 1H), 7.55-7.51 (m, 1H), 7.43-7.38 (m, 2H), 7.31-
7
1
.10 (d, J = 8.4 Hz, 2H), 7.05-7.03 (m, 1H), 6.89 (s, 2H), 6.86-6.82 (m, 7.29 (m, 1H), 7.17 (t, J = 8.0 Hz, 2H), 7.07-7.05 (m, 1H), 6.90 (s, 2H),
H), 5.45 (s, 1H), 2.61 (q, J = 7.6 Hz, 2H), 1.25 (s, 18H), 1.20 (t, J = 7.6 6.89-6.85 (m, 1H), 5.52 (s, 1H), 1.28 (s, 18H). 13C NMR (100 MHz,
Hz, 3H). 13C NMR (100 MHz, CDCl
; δ, ppm) 160.8, 157.3, 155.2, CDCl
45.2, 145.1, 135.7, 133.9, 133.6, 129.4, 128.1, 125.7, 124.8, 122.1, 131.6, 130.0, 129.2, 128.5, 125.3, 123.6, 121.9, 121.5, 121.0, 119.1,
3
3
; δ, ppm) 160.9, 158.3, 155.6, 148.1, 136.2, 134.1, 134.0,
1
1
2
-
1
-1
20.9, 118.8, 34.2, 30.0, 28.5, 15.7. IR (KBr, ν, cm ) 3481, 3409, 34.3, 30.0. IR (KBr, ν, cm ) 3566,3418, 2946, 1559, 1507, 1472,
962, 1576, 1507, 1437, 1230, 1112, 736. HRMS (ESI) m/z: [M-H]- 1236, 1115, 770. HRMS (ESI) m/z: [M-H] Calcd for C27
-
H29BrNO
3
Calcd for C29
Z)-N-((3,5-di-tert-butyl-4-hydroxyphenyl)(2-hydroxyphenyl)
methylene)-4-fluoroaniline oxide (3f)
H
34NO
3
444.2539; Found 444.2544.
494.1331; Found 494.1321.
(Z)-N-((3,5-di-tert-butyl-4-hydroxyphenyl)(2-hydroxy-5-
methylphenyl)methylene)aniline oxide (3k)
(
o
1
o
1
Yellow solid, 36 mg, 41%; mp 257-258 C; H NMR (400 MHz, CDCl
3
;
3
Yellow solid, 52 mg, 60%; mp 206-207 C; H NMR (400 MHz, CDCl ;
δ, ppm) 7.54-7.50 (m, 1H), 7.34-7.31 (m, 2H), 7.20-7.17 (m, 1H), δ, ppm) 7.33-7.29 (m, 4H), 7.28-7.26 (m, 2H), 7.08 (d, J = 8.4 Hz,
7
(
1
6
1
3
.04-6.96 (m, 3H), 6.89 (s, 2H), 6.88-6.84 (m, 1H), 5.51 (s, 1H), 1.27 1H), 6.89 (s, 2H), 6.79 (d, J = 2.0 Hz, 1H), 5.47 (s, 1H), 2.21 (s, 3H),
s, 18H). 13C NMR (100 MHz, CDCl
; δ, ppm) 162.0(1JCF = 230.4 Hz), 1.25 (s, 18H). 13C NMR (100 MHz, CDCl
; δ, ppm) 158.7, 157.5,
3
3
4
60.6, 157.9, 155.4, 144.9, 143.5, 138.6, 136.0, 134.9, 133.9( JCF
=
155.2, 147.4, 135.7, 134.9, 133.3, 129.5, 128.8, 128.5, 127.9, 125.6,
.0 Hz), 131.2, 129.3, 126.9(3JCF = 8.7 Hz), 125.5, 121.8, 121.0, 125.0, 121.6, 120.6, 34.2, 30.0, 20.4. IR (KBr, ν, cm ) 3481, 3420,
-1
19.0, 115.6(2JCF = 23 Hz), 107.2, 34.3, 30.0. IR (KBr, ν, cm ) 3545, 2961, 1497, 1456, 1231, 1097, 766. HRMS (ESI) m/z: [M-H] Calcd
-1
-
420, 2963, 1558, 1507, 1436, 1234, 1114, 773. HRMS (ESI) m/z: for C28
H
32NO
3
430.2382; Found 430.2371.
-
[
M-H] Calcd for C27
H29FNO
3
434.2131; Found 434.2147.
(Z)-N-((5-(tert-butyl)-2-hydroxyphenyl)(3,5-di-tert-butyl-4-
hydroxyphenyl)methylene)aniline oxide (3l)
(
Z)-4-chloro-N-((3,5-di-tert-butyl-4-hydroxyphenyl)(2-
o
1
hydroxyphenyl)methylene)aniline oxide (3g)
3
Yellow solid, 40 mg, 42%; mp 200-201 C; H NMR (400 MHz, CDCl ;
δ, ppm) 10.98 (s, 1H), 7.56-7.53 (m, 1H), 7.37-7.34 (m, 2H), 7.33-
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ARTICLE
Journal Name
7
2
.29 (m, 3H), 7.10 (d, J = 8.8 Hz, 1H), 6.93 (d, J = 2.4 Hz, 1H), 6.89 (s, NMR (100 MHz, CDCl
3
; δ, ppm) 160.1, 156.1, 155.6, 145.6, 144.9,
View Article Online
H), 5.48 (s, 1H), 1.24 (s, 18H), 1.17 (s, 9H). 13C NMR (100 MHz, 136.2, 135.9, 135.6, 129.5, 128.2, 124.9, 124.7, 124.0, 122.9, 110.5,
DOI: 10.1039/C8GC03593H
-1
3
CDCl ; δ, ppm) 158.7, 157.8, 155.3, 147.5, 141.2, 135.6, 131.2, 34.3, 30.0, 28.6, 15.7. IR (KBr, ν, cm ) 3560, 3421, 2957, 1581, 1469,
1
3
1
30.6, 129.8, 128.8, 128.6, 125.5, 125.0, 121.2, 120.2, 34.2, 34.0, 1439, 1226, 1137, 789. HRMS (ESI) m/z: [M-H]- Calcd for
-
1
1.3, 30.0. IR (KBr, ν, cm ) 3631, 3415, 2953, 1486, 1437, 1238,
29 3
C H33BrNO 522.1644; Found 522.1640.
-
155, 765. HRMS (ESI) m/z: [M-H] Calcd for C31
H38NO
3
472.2852; (Z)-3-bromo-N-((5-bromo-2-hydroxyphenyl)(3,5-di-tert-butyl-4-
Found 472.2866.
Z)-N-((3,5-di-tert-butyl-4-hydroxyphenyl)(2-hydroxy-5-
methoxyphenyl)methylene)aniline oxide (3m)
hydroxyphenyl)methylene)aniline oxide (3r)
Yellow solid, 62 mg, 54%; mp 157-158 C; H NMR (400 MHz, CDCl ;
3
δ, ppm) 10.94 (s, 1H), 7.61-7.58 (m, 1H), 7.43-7.40 (m, 2H), 7.28-
7.26 (m, 1H), 7.20-7.16 (m, 2H), 7.07 (d, J = 8.8 Hz, 1H), 6.88 (s, 2H),
o
1
(
o
1
3
Yellow solid, 49 mg, 55%; mp 150-151 C; H NMR (400 MHz, CDCl ;
δ, ppm) 11.42 (s, 1H), 7.34-7.29 (m, 4H), 7.28-7.26 (m, 2H), 7.07- 5.58 (s, 1H), 1.29 (s, 18H). 13C NMR (100 MHz, CDCl
.05 (m, 1H), 6.88 (s, 2H), 6.77 (t, J = 8.0 Hz, 1H), 6.62-6.59 (m, 1H), 157.1, 156.0, 148.0, 136.7, 136.4, 135.5, 131.9, 130.1, 129.3, 128.3,
.45 (s, 1H), 3.99 (s, 3H), 1.24 (s, 18H). 13C NMR (100 MHz, CDCl ; δ, 124.5, 123.5, 123.4, 123.0, 122.0, 110.8, 34.3, 30.0. IR (KBr, ν, cm-1)
3
; δ, ppm) 160.1,
7
5
3
ppm) 157.9, 155.2, 151.5, 151.0, 147.2, 135.7, 129.4, 128.8, 128.6, 3562, 2423, 2958, 1581, 1465, 1438, 1227, 1136, 788. HRMS (ESI)
-
1
25.6, 125.3, 125.0, 122.1, 118.3, 114.1, 56.2, 34.2, 30.0. IR (KBr, ν, m/z: [M-H] Calcd for C27
H28Br NO
2 3
572.0436; Found 572.0442.
-1
cm ) 3482, 3420, 2957, 2507, 2456, 1249, 1112, 767. HRMS (ESI) (Z)-N-((3,5-di-tert-butyl-4-hydroxyphenyl)(2-hydroxy-4-
-
m/z: [M-H] Calcd for C28
H32NO
4
446.2331; Found 466.2307.
methylphenyl)methylene)aniline oxide (3s)
Yellow solid, 63 mg, 73%; mp 264-265 C; H NMR (400 MHz, CDCl ;
3
o
1
(
Z)-N-((3,5-di-tert-butyl-4-hydroxyphenyl)(5-fluoro-2-
hydroxyphenyl)methylene)aniline oxide (3n)
Yellow solid, 54 mg, 62%; mp 197-198 C; H NMR (400 MHz, CDCl
δ, ppm) 7.32-7.29 (m, 5H), 7.27-7.22 (m, 1H), 7.15-7.12 (m, 1H), 18H). 13C NMR (100 MHz, CDCl
δ, ppm) 7.31-7.29 (m, 1H), 7.29-7.23 (m, 4H), 6.99 (s, 1H), 6.91 (d, J
= 6.4 Hz, 3H), 6.67-6.65 (m, 1H), 5.46 (s, 1H), 2.40 (s, 3H), 1.25 (s,
o
1
3
;
3
; δ, ppm) 160.9, 157.7, 155.2, 147.3,
6
.89 (s, 2H), 6.75-6.72 (m, 1H), 5.50 (s, 1H), 1.26 (s, 18H). 13C NMR 145.0, 135.8, 133.7, 129.4, 128.7, 128.7, 128.5, 125.7, 125.0, 121.1,
; δ, ppm) 156.9, 156.3(4JCF = 2.6 Hz), 155.5, 120.3, 119.1, 34.2, 30.0, 21.6. IR (KBr, ν, cm ) 3483, 3419, 2954,
-1
(100 MHz, CDCl
3
55.3(1JCF = 235.2 Hz), 147.2, 136.1, 129.2, 128.8, 125.0, 124.8, 1558, 1438, 1223, 1097, 768. HRMS (ESI) m/z: [M-H] Calcd for
-
1
1
3
1
22.4(3JCF = 7.8Hz), 122.1, 122.0, 121.3, 121.1, 118.2( JCF = 24.3 Hz),
2
28 3
C H32NO 430.2382; Found 430.2358.
-1
4.2, 30.0. IR (KBr, ν, cm ) 3481, 2414, 2958, 1507, 1465, 1239, (Z)-N-((3,5-di-tert-butyl-4-hydroxyphenyl)(2-hydroxy-4-
-
190, 765. HRMS (ESI) m/z: [M-H] Calcd for C27
H
29FNO
3
434.2131; methoxyphenyl)methylene)aniline oxide (3t)
o
1
Found 434.2135.
Z)-N-((5-chloro-2-hydroxyphenyl)(3,5-di-tert-butyl-4-
hydroxyphenyl)methylene)aniline oxide (3o)
3
Yellow solid, 46 mg, 51%; mp 254-255 C; H NMR (400 MHz, CDCl ;
(
δ, ppm) 12.11 (s, 1H), 7.31-7.29 (m, 1H), 7.28-7.24 (m, 4H), 6.92 (d, J
= 9.6 Hz, 3H), 6.66 (d, J = 2.4 Hz, 1H), 6.45-6.42 (m, 1H), 5.45 (s, 1H),
o
1
3.88 (s, 3H), 1.25 (s, 18H). 13C NMR (100 MHz, CDCl
Yellow solid, 58 mg, 64%; mp 240-241 C; H NMR (400 MHz, CDCl
3
;
3
; δ, ppm) 165.0,
δ, ppm) 7.47-7.44 (m, 1H), 7.31 (d, J = 6.8 Hz, 6H), 7.13 (d, J = 8.8 163.7, 157.8, 155.3, 147.2, 135.8, 135.2, 129.5, 128.7, 128.3, 125.6,
-1
Hz, 1H), 7.01 (d, J = 2.8 Hz, 1H), 6.88 (s, 2H), 5.52 (s, 1H), 1.26 (s, 125.1, 114.6, 108.0, 103.5, 100.0, 55.5, 34.2, 30.0. IR (KBr, ν, cm )
1
1
3
1
8H). 13C NMR (100 MHz, CDCl
3
; δ, ppm) 159.5, 156.5, 155.6, 147.2, 3545, 3422, 2958, 1616, 1517, 1436, 1231, 1119, 768. HRMS (ESI)
-
36.1, 133.6, 132.5, 129.4, 128.8, 124.9, 124.8, 123.6, 123.2, 122.5, m/z: [M-H] Calcd for C28
H32NO
4
446.2331; Found 446.2326.
-1
4.3, 30.0. IR (KBr, ν, cm ) 3481, 3416, 2964, 1559, 1456, 1222, (Z)-N-((3,5-di-tert-butyl-4-hydroxyphenyl)(4-fluoro-2-
-
095, 767. HRMS (ESI) m/z: [M-H] Calcd for C27
H29ClNO
3
450.1836; hydroxyphenyl)methylene)aniline oxide (3u)
o
1
Found 450.1830..
Z)-N-((5-bromo-2-hydroxyphenyl)(3,5-di-tert-butyl-4-
hydroxyphenyl)methylene)aniline oxide (3p)
Pale yellow solid, 76 mg, 87%; mp 237-238 C; H NMR (400 MHz,
CDCl ; δ, ppm) 7.30 (m, 4H), 7.28-7.26 (m, 1H), 7.03 (m, 1H), 6.89 (s,
(
3
2H), 6.86 (m, 1H), 6.59 (m, 1H), 5.50 (s, 1H), 1.25 (s, 18H). 13C NMR
o
1
; δ, ppm) 167.0 (1JCF = 252.1 Hz), 163.4, 163.3,
Yellow solid, 68 mg, 69%; mp 241-242 C; H NMR (400 MHz, CDCl
δ, ppm) 7.60-7.57 (m, 1H), 7.31 (d, J = 6.8 Hz, 6H), 7.15 (d, J = 2.4 157.4, 155.5, 147.0, 136.0, 135.7, 135.6, 129.4, 128.7 ( JCF = 12.0
Hz, 1H), 7.07 (d, J = 8.8 Hz, 1H), 6.88 (s, 2H), 5.52 (s, 1H), 1.26 (s, Hz), 125.3, 124.9, 118.5 (4JCF = 2.4 Hz), 107.4, 107.2 ( JCF = 19.0 Hz)
1
1
3
7
4
3
;
(100 MHz, CDCl
3
3
2
8H). 13C NMR (100 MHz, CDCl
; δ, ppm) 160.1, 156.4, 155.7, 147.2, 107.0, 34.2, 30.0. IR (KBr, ν, cm ) 3539, 3425, 2961, 1584, 1514,
-1
3
-
36.4, 136.1, 135.6, 129.5, 128.9, 124.8, 123.8, 122.9, 110.6, 34.3, 1420, 1235, 1118, 768. HRMS (ESI) m/z: [M-H] Calcd for C27
H29FNO
3
-1
0.0. IR (KBr, ν, cm ) 3482, 3417, 2954, 1558, 1473, 1222, 1095, 434.2131; Found 434.2132.
-
67. HRMS (ESI) m/z: [M-H] Calcd for C27
H29BrNO
3
494.1331; Found (Z)-N-((4-chloro-2-hydroxyphenyl)(3,5-di-tert-butyl-4-
94.1312.
hydroxyphenyl)methylene)aniline oxide (3v)
o
1
(
Z)-N-((5-bromo-2-hydroxyphenyl)(3,5-di-tert-butyl-4-
3
Yellow solid, 80 mg, 89%; mp 260-261 C; H NMR (400 MHz, CDCl ;
hydroxyphenyl)methylene)-4-ethylaniline oxide (3q)
Yellow solid, 71 mg, 68%; mp 193-194 C; H NMR (400 MHz, CDCl ;
3
δ, ppm) 11.58 (s, 1H), 7.31-7.29 (m, 4H), 7.29-7.26 (m, 1H), 7.19 (d, J
= 2.0 Hz, 1H), 6.97 (d, J = 8.8 Hz, 1H), 6.88 (s, 2H), 6.84-6.82 (m, 1H),
o
1
δ, ppm) 7.58-7.56 (m, 1H), 7.22-7.19 (m, 2H), 7.15 (d, J = 2.4 Hz, 1H), 5.51 (s, 1H), 1.25 (s, 18H). 13C NMR (100 MHz, CDCl
.12 (d, J = 8.4 Hz, 2H), 7.07 (d, J = 8.8 Hz, 1H), 6.87 (s, 2H), 5.52 (s, 157.2, 155.5, 147.1, 139.9, 136.0, 134.7, 129.3, 128.8, 128.8, 125.1,
3
; δ, ppm) 161.7,
7
1
H), 2.62 (q, J = 7.6 Hz, 2H), 1.26 (s, 18H), 1.20 (t, J = 7.6 Hz, 3H). 13
C
124.9, 121.0, 120.6, 119.4, 34.2, 30.0. IR (KBr, ν, cm ) 3546, 3415,
-1
6
| J. Name., 2012, 00, 1-3
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Journal Name
ARTICLE
2
960, 1559, 1507, 1436, 1224, 1119, 768. HRMS (ESI) m/z: [M-H]- (Z)-3-bromo-N-((4-chloro-2-hydroxyphenyl)(3,5-di-tert-butyl-4-
View Article Online
Calcd for C27
Z)-N-((4-chloro-2-hydroxyphenyl)(3,5-di-tert-butyl-4-
hydroxyphenyl)methylene)-4-methylaniline oxide (3w)
H
29ClNO
3
450.1836; Found 450.1847.
hydroxyphenyl)methylene)aniline oxide (3bDbO)I: 10.1039/C8GC03593H
Yellow solid, 55 mg, 52%; mp 173-174 C; H NMR (400 MHz, CDCl )
3
δ 7.42-7.39 (m, 2H), 7.27-7.26 (m, 1H), 7.20-7.15 (m, 2H), 6.99 (d, J
= 8.8 Hz, 1H), 6.89 (s, 2H), 6.86-6.83 (m, 1H), 5.57 (s, 1H), 1.28 (s,
o
1
(
o
1
Yellow solid, 76 mg, 82%; mp 248-249 C; H NMR (400 MHz, CDCl
3
;
δ, ppm) 7.19-7.16 (m, 3H), 7.07 (d, J = 8.4 Hz, 2H), 6.97 (d, J = 8.8 18H). 13C NMR (100 MHz, CDCl
3
; δ, ppm) 161.8, 157.9, 155.9, 147.9,
Hz, 1H), 6.87 (s, 2H), 6.83-6.81 (m, 1H), 5.49 (s, 1H), 2.32 (s, 3H), 140.3, 136.4, 134.7, 131.7, 130.1, 129.2, 128.4, 124.8, 123.5, 121.9,
-1
1
1
1
2
.25 (s, 18H). 13C NMR (100 MHz, CDCl
3
; δ, ppm) 161.7, 156.9, 121.1, 120.2, 119.6, 34.3, 30.0. IR (KBr, ν, cm ) 3529, 3412, 2955,
-
55.4, 144.7, 139.7, 139.0, 136.0, 134.7, 129.3, 129.2, 125.3, 124.7, 1584, 1508, 1437, 1224, 1111, 726. HRMS (ESI) m/z: [M-H] Calcd
-1
21.0, 120.7, 119.3, 34.2, 30.0, 21.0. IR (KBr, ν, cm ) 3558, 3477, for C27
856, 1572, 1511, 1384, 1221, 1106, 912. HRMS (ESI) m/z: [M-H]- (Z)-N-((4-bromo-2-hydroxyphenyl)(3,5-di-tert-butyl-4-
464.1992; Found 464.2001. hydroxyphenyl)methylene)aniline oxide (3cc)
Z)-N-((4-chloro-2-hydroxyphenyl)(3,5-di-tert-butyl-4-
hydroxyphenyl)methylene)-3-methylaniline oxide (3x)
3
H28BrClNO 528.0941; Found 528.0930.
Calcd for C28H31ClNO
3
(
o
1
3
Yellow solid, 55 mg, 56%; mp 258-259 C; H NMR (400 MHz, CDCl ;
δ, ppm) 11.56 (s, 1H), 7.37 (d, J = 2.0 Hz, 1H), 7.30 (d, J = 6.8 Hz, 5H),
6.99-6.96 (m, 1H), 6.89 (d, J = 10.8 Hz, 3H), 5.50 (s, 1H), 1.25 (s,
o
1
3
Yellow solid, 75 mg, 81%; mp 191-192 C; H NMR (400 MHz, CDCl ;
δ, ppm) 7.19 (d, J = 2.0 Hz, 1H), 7.14 (d, J = 7.2 Hz, 1H), 7.11-7.05 18H). 13C NMR (100 MHz, CDCl
3
; δ, ppm) 161.6, 157.3, 155.5, 147.1,
m, 3H), 6.99 (d, J = 8.8 Hz, 1H), 6.88 (s, 2H), 6.84-6.81 (m, 1H), 5.50 136.0, 134.7, 129.3, 128.8, 128.8, 128.4, 125.1, 124.9, 124.1, 122.2,
(
(
s, 1H), 2.25 (s, 3H), 1.26 (s, 18H). 13C NMR (100 MHz, CDCl
) δ 161.7, 157.1, 155.5, 146.9, 139.8, 1436, 1224, 1121,768. HRMS (ESI) m/z: [M-H]- Calcd for
38.9, 136.0, 134.7, 129.4, 129.2, 128.6, 125.5, 125.3, 121.9, 121.0, 494.1331; Found 494.1333.
; δ, 121.0, 34.2, 30.0. IR (KBr, ν, cm ) 3547, 3421, 2959, 1585, 1558,
-1
3
ppm) 13C NMR (101 MHz, CDCl
3
1
1
1
27 3
C H29BrNO
-1
20.6, 119.4, 34.2, 30.0, 21.0. IR (KBr, ν, cm ) 3550, 3426, 2958, (Z)-N-((3,5-di-tert-butyl-4-hydroxyphenyl)(2-hydroxy-3-
587, 1508, 1439, 1224, 1121, 793. HRMS (ESI) m/z: [M-H] Calcd methoxyphenyl)methylene)aniline oxide (3dd)
-
o
1
for C28
H31ClNO
3
464.1992; Found 464.1996.
3
Yellow solid, 44 mg, 49%; mp 152-153 C; H NMR (400 MHz, CDCl ;
(
Z)-N-((4-chloro-2-hydroxyphenyl)(3,5-di-tert-butyl-4-
δ, ppm) 7.33-7.29 (m, 4H), 7.28-7.26 (m, 2H), 7.07-7.05 (m, 1H),
6.88 (s, 2H), 6.78 (t, J = 8.0 Hz, 1H), 6.62-6.60 (m, 1H), 5.45 (s, 1H),
hydroxyphenyl)methylene)-4-ethylaniline oxide (3y)
Yellow solid, 70 mg, 73%; mp 241-242 C; H NMR (400 MHz, CDCl
o
1
3.99 (s, 3H), 1.24 (s, 18H). 13C NMR (100 MHz, CDCl
3
;
3
; δ, ppm) 157.9,
δ, ppm) 7.21-7.18 (m, 3H), 7.10 (d, J = 8.4 Hz, 2H), 6.97 (d, J = 8.8 155.2, 151.5, 151.0, 147.2, 135.7, 129.4, 128.8, 128.6, 125.6, 125.3,
-1
Hz, 1H), 6.88 (s, 2H), 6.84-6.81 (m, 1H), 5.49 (s, 1H), 2.61 (q, J = 7.6 125.0, 122.1, 118.3, 114.1, 56.2, 34.2, 30.0. IR (KBr, ν, cm ) 3468,
Hz, 2H), 1.25 (s, 18H), 1.19 (t, J = 7.6 Hz, 3H). 13C NMR (100 MHz, 3412, 2957, 1507, 1436, 1249, 1112, 688. HRMS (ESI) m/z: [M-H]-
CDCl
3
; δ, ppm) 161.7, 156.9, 155.5, 145.5, 144.8, 139.7, 135.9, Calcd for C28
H
32NO
4
446.2331; Found 446.2326.
General procedure for the synthesis of product 5a
Z)-N-((3,5-di-tert-butyl-4-hydroxyphenyl)(2-hydroxyphenyl)
methylene)aniline oxide (3a, 0.1 mmol, 41.7 mg), dimethyl but-2-
ynedioate (0.15 mmol, 21.3 mg), Et N (0.1 mmol, 10.1 mg) were
added in a 10-mL reaction vial. Then, CH CN (3.0 mL) was added
1
2
1
4
34.7, 129.4, 128.2, 125.2, 124.7, 121.0, 120.7, 119.3, 34.2, 30.0,
8.5, 15.7. IR (KBr, ν, cm ) 3554, 3427, 2960, 1568, 1508, 1424,
224, 1115, 847. HRMS (ESI) m/z: [M-H] Calcd for C29
78.2149; Found 478.2150.
-1
(
-
H33ClNO
3
3
(
Z)-3-chloro-N-((4-chloro-2-hydroxyphenyl)(3,5-di-tert-butyl-4-
hydroxyphenyl)methylene)aniline oxide (3z)
Yellow solid, 82 mg, 85%; mp 183-184 C; H NMR (400 MHz, CDCl
δ, ppm) 7.28-7.22 (m, 3H), 7.21-7.20 (m, 1H), 7.19 (d, J = 2.0 Hz, at 80 C for 12 h until TLC (petroleum ether: ethyl acetate= 5:1)
3
o
1
3
;
into this reaction system. The reaction vial was sealed and heated
o
1
1
1
1
3
H), 6.99 (d, J = 8.8 Hz, 1H), 6.89 (s, 2H), 6.85-6.83 (m, 1H), 5.57 (s, revealed that conversion of the starting material 3a was completed.
H), 1.28 (s, 18H). 13C NMR (100 MHz, CDCl
55.9, 147.8, 140.3, 136.4, 134.8, 134.5, 129.8, 129.2, 128.9, 125.5,
; δ, ppm) 161.8, 157.8,
3
Then the reaction mixture was extracted concentrated by vacuum
distillation and was purified by flash column chromatography (silica
gel, mixtures of petroleum ether / acetic ester, 15:1, v/v) to afford
the pure products 5a (48 mg, 86%) as orange solid.
-1
24.8, 123.1, 121.1, 120.2, 119.6, 34.3, 30.0. IR (KBr, ν, cm ) 3555,
451, 2959, 1584, 1508, 1437, 1224, 1120, 789. HRMS (ESI) m/z:
-
[
M-H] Calcd for C27
H28Cl
2
NO
3
484.1446; Found 484.1470.
(
Z)-3,4-dichloro-N-((4-chloro-2-hydroxyphenyl)(3,5-di-tert-butyl-4-
Dimethyl
hydroxyphenyl) -2-phenyl-2,3-dihydroisoxazole-4,5-dicarboxylate
5a)
Orange solid, 48 mg, 86%; mp 142-143 C; H NMR (400 MHz, CDCl
δ, ppm) 7.37-7.35 (m, 1H), 7.27-7.18 (m, 3H), 7.10 (d, J = 8.0 Hz,
3-(3,5-di-tert-butyl-4-hydroxyphenyl)-3-(2-
hydroxyphenyl)methylene)aniline oxide (3aa)
Yellow solid, 75 mg, 72%; mp 205-206 C; H NMR (400 MHz, CDCl
δ 7.39-7.35 (m, 2H), 7.19 (d, J = 2.0 Hz, 1H), 7.17 (m, 1H), 6.99 (d, J =
8
1
1
1
1
o
1
3
)
(
o
1
3
;
.8 Hz, 1H), 6.89 (s, 2H), 6.86-6.84 (m, 1H), 5.60 (s, 1H), 1.29 (s,
8H). 13C NMR (100 MHz, CDCl
; δ, ppm) 161.8, 158.1, 156.1, 145.9,
40.5, 136.6, 134.7, 133.0, 132.8, 130.3, 129.2, 127.2, 124.7, 124.1,
3
2
4
H), 7.01 (d, J = 8.4 Hz, 3H), 6.97-6.93 (m, 1H), 6.86-6.83 (m, 1H),
.99 (s, 1H), 4.90 (s, 1H), 3.91 (s, 3H), 3.31 (s, 3H), 1.37 (s, 18H). 13
C
-1
21.2, 120.1, 119.7, 34.3, 30.0. IR (KBr, ν, cm ) 3553, 3428, 2953,
3
NMR (100 MHz, CDCl ; δ, ppm) 169.8, 164.9, 153.1, 149.8, 147.8,
-
560, 1501, 1438, 1222, 1120, 885. HRMS (ESI) m/z: [M-H] Calcd
1
1
36.4, 131.5, 129.0, 127.2, 122.0, 122.0, 121.2, 119.7, 119.1, 117.4,
16.5, 95.9, 54.0, 51.5, 34.5, 30.2. IR (KBr, ν, cm ) 3614, 3428, 2958,
for C27
H27Cl
3
NO
3
518.1057; Found 518.1050.
-1
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 7
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Page 8 of 10
ARTICLE
Journal Name
1
754, 1684, 1593, 1435, 1361, 1257, 760. HRMS (ESI) m/z: [M-H]-
Calcd for C33 558.2492; Found 558.2497.
3
(a) L. Wang, L.-X. Shi, L. Liu, Z.-X. Li, T. Xu, W.-J. VHieawoA,rtGic.leLOi,nlSin.e-
DOI: 10.1039/C8GC03593H
Liang, S. Song, L. Ai, X. Li and N. Jiao, Green Chem., 2016, 18,
J. Tu and B. Jiang, J. Org. Chem., 2017, 82, 3605; (b) Y.-F.
H36NO
7
6
462; (c) C. E. Garrett and K. Prasad, Adv. Synth. Catal., 2004,
46, 889; (d) C. J. Welch, J. Albaneze-Walker, W. R. Leonard,
General procedure for the synthesis of product 6a
Z)-N-((3,5-di-tert-butyl-4-hydroxyphenyl)(2-hydroxyphenyl)
methylene)aniline oxide (3a, 0.1 mmol, 41.7 mg), 1,3-diphenylprop-
-yn-1-one (0.15 mmol, 30.9 mg), Et N (0.1 mmol, 10.1 mg) were
added in a 25-mL reaction vial, Then, CH CN (3.0 mL) was added
3
(
M. Biba, J. DaSilva, D. Henderson, B. Laing, D. J. Mathre, S.
Spencer, X. Bu and T. Wang, Org. Process Res. Dev., 2005, 9,
1
98; (e) H.-K. Sha, F. Liu, J. Lu, Z.-Q. Liu, W.-J. Hao, J.-L. Tang,
2
3
S.-J. Tu and B. Jiang, Green Chem., 2018, 20, 3476. (f) Z.-J.
Shen, Y.-N. Wu, C.-L. He, L. He, W.-J. Hao, A.-F. Wang, S.-J. Tu
and B. Jiang, Chem. Commun., 2018, 54, 445-448
3
into this reaction system. The reaction vial was sealed and heated
o
4
(a) C.-L. Sun and Z.-J. Shi, Chem. Rev., 2014, 114, 9219-9280;
at 100 C for 12 h until TLC (petroleum ether: ethyl acetate= 5:1)
(
b) A. Bhunia, S. R. Yetra and A. T. Biju, Chem. Soc. Rev.,
revealed that conversion of the starting material 3a was completed.
Then the reaction mixture was extracted concentrated by vacuum
distillation and was purified by flash column chromatography (silica
gel, mixtures of petroleum ether / acetic ester, 15:1, v/v) to afford
the pure products 6a (33 mg, 53%) as yellow solid.
2
012, 41, 3140; (c) C. Allais, J.-M. Grassot, J. Rodriguez and T.
Constantieux, Chem. Rev., 2014, 114, 10829; (d) S. Wertz and
A. Studer, Green Chem., 2013, 15, 3116; (e) S. S. Bhojgude
and A. T. Biju, Angew. Chem., Int. Ed., 2012, 51, 1520; (f) K.
Chen, P. Zhang, Y. Wang and H. Li, Green Chem. 2014, 16,
2
344; (g) F. Liu, J.-Y. Wang, P. Zhou, G. Li, W.-J. Hao, S.-J. Tu
and B. Jiang, Angew. Chem., Int. Ed., 2017, 56, 15570.
(
3-(3,5-di-tert-butyl-4-hydroxyphenyl)-3-(2-hydroxyphenyl)-2,5-
5
6
(a) C.-J. Li, Chem. Rev., 2005, 105, 3095; (b) C.-J. Li, Chem.
Rev., 1993, 93, 2023; (c) C.-J. Li and L. Chen, Chem. Soc. Rev.,
2006, 35, 68. (d) M.-O. Simon and C.-J. Li, Chem. Soc. Rev.,
diphenyl-2,3-dihydroisoxazol-4-yl)(phenyl)-methanone (6a)
Yellow solid, 33 mg, 53%; mp 167-168 C; H NMR (400 MHz, CDCl
δ, ppm) 8.17 (d, J = 7.2 Hz, 2H), 7.69 (d, J = 7.6 Hz, 2H), 7.61-7.58
o
1
3
;
2
012, 41, 1415; (e) L.-Y. Xie, Y. Duan, L.-H. Lu, Y.-J. Li, S. Peng,
C. Wu, K.-J. Liu, Z. Wang and W.-M. He, ACS Sus. Chem. Eng.,
017, 5, 10407; (f) C. Wu, X. Xin, Z.-M. Fu, L.-Y. Xie, K.-J. Liu,
Z. Wang, W. Z.-H. Li, Yuan and W.-M. He, Green Chem., 2017,
9, 1983.
(m, 1H), 7.45-7.35 (m, 5H), 7.27-7.18 (m, 4H), 7.18-7.04 (m, 5H),
2
1
3
6
.88 (s, 2H), 6.30 (s, 1H), 5.11 (s, 1H), 1.29 (s, 18H). C NMR (100
; δ, ppm) 188.5, 163.7, 157.7, 151.9, 148.2, 145.3, 140.7,
36.6, 133.4, 132.1, 131.0, 130.3, 129.7, 129.4, 129.0, 128.7, 128.5,
27.9, 127.8, 127.1, 125.6, 124.9, 124.4, 122.2, 104.2, 34.3, 30.0. IR
1
MHz, CDCl
1
1
3
For reviews on the nitrone chemistry, see: (a) R. C. F. Jones
and J. N. Martin, In Synthetic Applications of 1,3-Dipolar
Cycloaddition Chemistry Toward Heterocycles and Natural
Products, The Chemistry of Heterocyclic Compounds, Vol. 59;
A. Padwa and W. H. Pearson, Eds.; Wiley: New York, 2002; pp
-1
(KBr, ν, cm ) 3612, 3420, 2972, 1733, 1525, 1481, 1427, 1214, 701.
-
HRMS (ESI) m/z: [M-H] Calcd for C42
6
H40NO
4
622.2957; Found
1
−87; (b) K. Rück-Braun, T. H. E. Freysoldt and F. Wieschem,
22.2958.
Chem. Soc. Rev., 2005, 34, 507; (c) F. Cardona and A. Goti,
Angew. Chem., Int. Ed., 2005, 44, 7832; (d) L. L. Anderson,
Asian J. Org. Chem., 2016, 5, 9; (d) W.-M. Shi, X.-P. Ma, G.-F.
Su and D.-L. Mo, Org. Chem. Front., 2016, 3, 116; (f) D. B.
Huple, S. Ghorpade, and R.-S. Liu, Adv. Synth. Catal., 2016,
Acknowledgements
We are grateful for financial support from the NSFC (Nos. 21602087
and 21871112), the Outstanding Youth Fund of JSNU (YQ2015003),
NSF of Jiangsu Province (BK20160212), the Qing Lan Project of
Jiangsu Education Committee (QL2016006), and the Graduate
Education Innovation Project of Jiangsu Province (KYCX18_2104).
3
58, 1348.
7
8
For [3+2] cyclodditions of nitrones, see: (a) G.-H. Li, W. Zhou,
X.-X. Li, Q.-W. Bi, Z. Wang, Z.-G. Zhao, W.-X. Hu and Z. Chen,
Chem. Commun., 2013, 49, 4770; (b) D. Zhang, C.-K. Yin, Y.-H.
Zhou, Y.-L. Xu, L.-L. Lin, X.-H. Liu and X.-M. Feng, Chem.
Commun., 2017, 53, 7925; (c) X. Yang, F. Cheng, Y.-D. Kou, S.
Pang, Y. -C. Shen, Y. -Y. Huang and N. Shibata, Angew. Chem.
Int. Ed., 2017, 56, 1510.
For [3+3] cyclodditions of nitrones, see: (a) R. Shintani and T.
Hayashi, J. Am. Chem. Soc., 2006, 128, 6330; (b) R. Shintani,
S. Park, W.-L. Duan and T. Hayashi, Angew. Chem. Int. Ed.,
Notes and references
1
(a) B. M. Trost, Acc. Chem. Res., 2002, 35, 695; (b) S. Kotha,
D. Goyal and A. S. Chavan, J. Org. Chem., 2013, 78, 12288; (c)
K. Banert and O. Plefka, Angew. Chem., Int. Ed., 2011, 50,
2
007, 46, 5901; (c) F. Liu, Y. Yu and J. Zhang, Angew. Chem.
Int. Ed., 2009, 48, 5505; (d) F. Liu, D. Qian, L. Li, X. Zhao and J.
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Cheng, J. Yedoyan, H. Arman and M. P. Doyle, J. Am. Chem.
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6
171; (d) B. M. Trost, F. D. Toste and K. Greenman, J. Am.
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1
3, 2958; (g) M.-H. Huang, W.-J. Hao, G. Li, S.-J. Tu and B.
9
For [3+4] cycloaddition reactions of nitrones, see: (a)Y. Bai, J.
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Zhang, F. Liu and L. Zhang, Chem. Eur. J., 2010, 16, 6146; (c)
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2
For selected reviews: see (a) R. A. Sheldon, Green Chem.,
2
2
3
005, 7, 267; (b) A. Chanda and V. V. Fokin, Chem. Rev.,
009, 109, 725; (c) C.-J. Li and L. Chen, Chem. Soc. Rev., 2006,
5, 68; (d) M. B. Gawande, V. D. B. Bonifacio, R. Luque, P. S.
2
680. (e) X.-K. Zhang, Y. Pan, P, Liang, L, Pang, X.-F. Ma, W. J
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0 E. Buehler, J. Org. Chem., 1967, 32, 261.
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Branco and R. S. Varma, Chem. Soc. Rev., 2013, 42, 5522; (e)
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C.-J. Li and T.-H. Chan, Tetrahedron, 1999, 55, 11149; (g) M.-
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(
b) M. Shun-Ichi, M. Hitoshi, S. Tatsuki, T. Tomoyasu and S.
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2 S. Cicchi, A. Goti and A. Brandi, J. Org. Chem., 1995, 60, 4743.
8
| J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
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1
1
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3 D. Christensen and K. A. Jorgensen, J. Org. Chem., 1989, 54,
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5 V. Gautheron-Chapoulaud, S. U. Pandya, P. Cividino,G.
Masson, S. Py and Y. Vallée, Synlett, 2001, 8, 1281.
View Article Online
DOI: 10.1039/C8GC03593H
1
6 (a) X.-P. Ma, W.-M. Shi, X.-L. Mo, X.-H. Li, L.-G. Li, C.-X. Pan,
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Green Chemistry
Page 10 of 10
View Article Online
DOI: 10.1039/C8GC03593H
Metal-free synthesis of triarylated (Z)-nitrones via H O-mediated
2
1
,3-dipolar transfer under aerobic conditions
Ke Chen, Wen-Juan Hao, Shu-Jiang Tu, and Bo Jiang
HO
tBu
R1
tBu
tBu
Ar H O, 80 o
2
C
Ar
Ph
N
O
HO
O
N
O
O2 (1.0 atm)
R1
tBu
O
H
A new and environmentally benign protocol aimed at the generation of triarylated (Z)-nitrones in
generally good yield has been developed via metal- and catalyst-free H O-mediated 1,3-dipolar
2
transfer reaction of para-quinone methides (p-QMs) with diarylated nitrones under the aerobic
conditions.