Palladium-catalyzed chelation-assisted aromatic C-H nitration: Regiospecific synthesis of nitroarenes free from the effect of the orientation rules

Article abstract of DOI:10.1021/jo400594j

A palladium-catalyzed chelation-assisted ortho-nitration of aryl C-H bond is described. A range of azaarenes such as 2-arylquinoxalines, pyridines, quinoline, and pyrazoles were nitrated with excellent chemo- and regioselectivity. Using the O-methyl oximyl group as a removable directing group, the regiospecific synthesis of a variety of o-nitro aryl ketones was achieved starting from aryl ketones via a three-step process involving the Pd-catalyzed ipso-nitration of C-H bond as a key step. Mechanistic investigations support a silver-mediated radical mechanism involving Pd((II/III) and/or Pd(II/IV) catalytic cycles under oxidizing conditions.

Full text of DOI:10.1021/jo400594j

Article
pubs.acs.org/joc
Palladium-Catalyzed Chelation-Assisted Aromatic C−H Nitration:
Regiospecific Synthesis of Nitroarenes Free from the Effect of the
Orientation Rules
Wei Zhang, Shaojie Lou, Yunkui Liu,* and Zhenyuan Xu
State Key Laboratory Breeding Base of Green Chemistry-Synthesis Technology, Zhejiang University of Technology,
Hangzhou 310014, People’s Republic of China
S
* Supporting Information
ABSTRACT: A palladium-catalyzed chelation-assisted ortho-
nitration of aryl C−H bond is described. A range of azaarenes
such as 2-arylquinoxalines, pyridines, quinoline, and pyrazoles
were nitrated with excellent chemo- and regioselectivity. Using
the O-methyl oximyl group as a removable directing group,
the regiospecific synthesis of a variety of o-nitro aryl ketones
was achieved starting from aryl ketones via a three-step process
involving the Pd-catalyzed ipso-nitration of C−H bond as a key
step. Mechanistic investigations support a silver-mediated radical mechanism involving Pd((II/III) and/or Pd(II/IV) catalytic
cycles under oxidizing conditions.
carbon−heteroatom bonds.12 The excellent regioselectivity
achieved in these C−H functionalizations led us to envision a
INTRODUCTION
■
Aromatic nitro compounds are important synthetic precursors in
the chemical industry as well as in academic research.1 Since
Mitscherlich2 reported the first nitration of benzene with fuming
nitric acid in 1834, the nitrating agent-involved electrophilic
aromatic substitution has long been the predominant synthetic
approach for the preparation of nitroarenes.3 However, the
traditional electrophilic nitration processes are usually associated
with several persistent disadvantages including poor regioselec-
tivity, poor chemoselectivity arising from overnitration, imperfect
functional group and/or substrate compatibility under acidic
conditions, nitration sites significantly depending on the
orientation effect of different functional groups, and the use of
environmentally harmful acid reagents.3 Therefore, it is still highly
desirable to develop new nitration methods that can overcome
the above-mentioned problems.
Until now, several new strategies, most focusing on
regiospecific synthesis of nitroarenes, have been developed.4,5
For example, ipso-oxidation of an amino6 or an azide7 to a nitro
group provides an indirect nitration protocol to introduce the
nitro group in regiospecific manner. Recently, ipso-nitration
protocol4 has received attention as a more attractive method for
the regiospecific synthesis of nitroarenes which can be achieved via
nitrodemetalation of an organometallic reagents (M = B, Li)5,8,9 or
via nitrodecarboxylation of an aryl carboxylic acid,10 or via
transition-metal-catalyzed (Cu or Pd) ipso-nitration of aryl halides,
pseudohalides, or aryl boronic acids.11 Despite the promising
prospects of these methods for the regiospecific synthesis of
nitroarenes, they all suffer from the use of prefunctionalized
starting materials.
regioselective and environmentally benign direct C−H nitration
of arenes that can avoid the prefunctionalized steps.8−11 In this
context, we have recently communicated the first palladium-
catalyzed chelation-assisted ortho-specific nitration of aromatic
C−H bonds mainly using N-heterocycles as the directing groups
which are difficult to be removed.13,14 For practical purposes, we
envision that using a removable or modifiable directing group15
has more advantages because it not only expands the scope of
substrates and products but also enables a site-regiospecific
introduction of the nitro group to the target functional
groups free from the effect of orientation rules which is difficult
to pursue via traditional methods. Herein, we detail our recent
efforts in developing palladium-catalyzed chelation-assisted site-
regiospecific nitration of aromatic C−H bonds, the practical
synthesis of o-nitro aryl ketones using removable directing
groups, and mechanistic studies.
RESULTS AND DISCUSSION
■
We commenced the study with the direct ortho-nitration of
aromatic C−H bonds using the quinoxaline moiety as the
directing group16 due to the potential utilities of quinoxaline
derivatives in materials science, chemical, and pharmaceutical
fields.17 2-Phenylquinoxaline 1a was selected as a model sub-
strate for optimizing the reaction conditions, and the results are
listed in Table 1. First, several palladium catalysts were surveyed
using AgNO2 (2 equiv) as a nitro source and K2S2O8 (2 equiv)
as an oxidant in DCE at 130 °C for 48 h. It was found that
In the last decades, transition-metal-catalyzed chelation-
assisted C−H functionalization has emerged as a powerful tool
for the regioselective construction of carbon−carbon and
Received: March 21, 2013
© XXXX American Chemical Society
A
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oxidants and solvents were examined. It was found that Oxone
and CAN could give moderate yields of 2a (entries 12, 13,
Table 1) while other oxidants (BQ, PhI(OAc)2), DDQ,
Cu(OAc)2, and CuCl2) showed low efficiency (entries 11, 14−17,
Table 1). Among several solvents so far surveyed, DCE was found to
be the best choice (entries 18−24, Table 1).
Table 1. Optimization of Reaction Conditions for Ortho-
Nitration of 1a
a
Under the established reaction conditions, the scope of the
Pd-catalyzed ortho-nitration of quinoxaline derivatives 1 with
AgNO2 was investigated (Table 2). A variety of quinoxaline
derivatives 1 could be smoothly ortho-nitrated to furnish the
desired nitration products 2 in moderate to good yields (35−
93%, entries 1−18 except 13 and 15, Table 2). Substrates 1
bearing electron-rich aryl rings generally afforded the desired
product in moderate to good yields (76−93%, entries 1−7,
Table 2). The protocol also enabled ortho-nitration of electron-
deficient aryl rings albeit with lower yields (35−51%, entries
8−10 and 12, Table 2). A thiophene-yl ring tethered with the
quinoxaline directing group could also be ortho-nitrated in 35%
yield (entry 14, Table 2). When quinoxaline derivatives 1m or 1o
was employed as a substrate, the reaction failed to furnish the
desired product while the starting substrate was recovered
quantitatively (entries 13, 15, Table 2). Note that the neutral
conditions could tolerate a series of functional groups, such as
methoxy, hydroxyl, acetoxy, and thiophene-yl groups (entries,
3−5, 6, 12, and 14, Table 2). Interestingly, a bromo substituent
survived under the palladium-catalyzed conditions and could be
further decorated (entry 10, Table 2). For the more challenging
nitrations of 2,3-diphenylquinoxalines 1q and 1r, double-
centered C−H nitration directed by each proximal nitrogen
donor in the quinoxaline ring was also achieved in high chemo-
selectivity (entries 17 and 18, Table 2). The ortho-regiochemistry
of the nitrating reaction was unambiguously established on the
basis of the spectral analyses, which was further confirmed by the
X-ray crystallography of 2c (see the Supporting Information).
Next, the generality of this protocol for other N-heterocycle-
assisted C−H nitration was examined. To our delight, the
2-pyridyl group could be equally employed as a directing group
for the C−H nitration of both electron-rich and electron-
deficient arenes, albeit with lower yields compared with the cases
of 2-quinoxalinyl group (4a−g, Figure 1). When 2-(naphthalen-
2-yl)pyridine 3g was tested, regioisomers 4g and 4g′ were
obtained in a total yield of 45% with a ratio of 1:1 (Figure 1).
Under the standard reaction conditions, it was found that
benzo[h]quinoline 3h and 1-phenyl-1H-pyrazole 3i gave only
trace amounts of the desired nitroarenes and the starting
substrates were recovered. However, when the oxidant was
switched to CAN, the ortho-nitration of 3h and 3i proceeded
smoothly and the desired products were obtained in 61% and
55% yield, respectively (Figure 1, 4h and 4i).
b
yield
(%)
entry
catalyst
PdCl2
oxidant
K2S2O8
MNO2
AgNO2
solvent
DCE
1
2
3
45
Pd(PPh3)2Cl2
K2S2O8
AgNO2
DCE
74
Pd(OAc)2
K2S2O8
AgNO2
DCE
91
c
(86 )
d
4
5
6
Pd(OAc)2
Pd(OAc)2
K2S2O8
K2S2O8
AgNO2
AgNO2
AgNO2
DCE
DCE
DCE
82 ,
e
41
f
80 ,
g
48 ,
Pd(OAc) /2,2′- K2S2O8
<5
2 h
bipyridyl
7
8
Pd(OAc)2
Pd(OAc)2
K2S2O8
NaNO2
NaNO2
DCE
DCE
31
42
K2S2O8/
Ag2O/
PivOH
i
9
Pd(OAc)2
K2S2O8
KNO2/18-
crown-6
DCE
<5
j
10
11
12
13
14
15
16
17
18
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
K2S2O8
(TBA)NO2 DCE
<5
0
k
BQ
AgNO2
AgNO2
AgNO2
AgNO2
AgNO2
AgNO2
AgNO2
AgNO2
DCE
DCE
DCE
DCE
DCE
DCE
DCE
1,4-
Oxone
88
76
trace
0
l
CAN
PhI(OAc)2
m
DDQ
Cu(OAc)2
CuCl2
24
0
K2S2O8
0
dioxane
19
20
21
22
23
24
25
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
AgNO2
AgNO2
AgNO2
AgNO2
AgNO2
AgNO2
AgNO2
DMF
0
toluene
MeNO2
MeCN
CH2Cl2
MeOH
DCE
0
0
0
86
0
0
a
Reaction conditions: 1a (0.3 mmol), [Pd] (0.03 mmol), MNO2
(0.06 mmol), oxidant (0.06 mmol) in 3.5 mL of solvent at 130 °C for 48
h unless otherwise noted. GC yields using phenanthrene as an internal
standard. Isolated yields. The reaction temperature is 110 °C. The
reaction temperature is 90 °C. 5 mol % of Pd(OAc)2 was used. In the
presence of AgNO2 (1 equiv) and K2S2O8 (1 equiv). 0.036 mmol
of 2,2′-bipyridyl. 2 equiv of Ag2O/PivOH. 18-Crown-6 (0.6 mmol)
was added as a phase-transfer catalyst (PTC). BQ = benzoquinone.
b
c
d
e
f
g
h
i
j
k
l
m
CAN = cerium ammonium nitrate. DDQ = 2,3-dichloro-5,6-
dicyano-1,4-benzoquinone.
After realizing ortho-nitration of aromatic C−H bonds assisted
by N-heterocycles which are difficult to be removed from the
final products, we further attempted to employ the present
strategy in the regioselective nitration of removable N-donor
tethered aromatics. Thus acetophenone O-methyl oxime 5a was
selected as a target substrate. We envision that the ortho-nitration
of 5a followed by removal of the O-methyl oximyl group18 of
the resulting nitrated product would open a novel access to
regiospecifically synthesize o-nitro acetophenone 7a, which is a
useful building block in synthetic organic chemistry.19 Owing
to the orientation effect of the carbonyl group,3 it is infeasible
that acetophenone itself regiospecifically transforms to 7a via
traditional electrophilic nitration processes.20
Pd(OAc)2 was superior to other palladium sources including
PdCl2 and Pd(PPh3)2Cl2, affording the desired nitroarene 2a in
91% GC yield and 86% isolated yield, respectively (entries 1−3,
Table 1). Decreasing the reaction temperature did not favor the
nitration (Table 1, entry 4). The reaction gave inferior results
when the catalyst loading (5 mol %) and the amount of AgNO2/
K2S2O8 (1 equiv), respectively, were decreased (entry 5, Table 1).
A combination of Pd(OAc)2 and 2,2′-bipyridyl (0.12 equiv) gave
trace amount of 2a (entry 6, Table 1). No reaction took place
in the absence of a palladium catalyst (entry 25, Table 1). Then,
a series of nitrites were surveyed, and AgNO2 was proven to be the
best choice (entries 7−10 vs 3, Table 1). Finally, the effects of
B
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a
Table 2. Pd-Catalyzed Ortho-Nitration of Quinoxaline Derivatives 1.
a
Reaction conditions: 1 (0.3 mmol), Pd(OAc)2 (0.03 mmol), AgNO2 (0.6 mmol), K2S2O8 (0.6 mmol) in 3.5 mL of DCE at 130 °C for 48 h.
Isolated yields. AgNO2 (0.3 mmol) and K2S2O8 (0.3 mmol) were used. AgNO2 (0.9 mmol), K2S2O8 (0.9 mmol), and Pd(OAc)2 (0.045 mmol)
b
c
d
were used.
When acetophenone O-methyl oxime 5a was subjected to the
above-mentioned conditions, 2-nitrated product 6a was indeed
obtained in 51% isolated yield (entry 1, Table 3). Through
carefully screening a series of parameters including palladium
C
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to that case of quinoxaline substrates (Table 2, vide supra). For
example, a series of fluoro-, chloro-, bromo-, iodo-, cyano-,
methylsulfonyl-, or even nitro-para-substituted phenyl rings
could be well ortho-nitrated to furnish the target products in
good to excellent yields (72−91%, entries, 9, 10, 12, 14−16, and
18, Table 4), while low (substituted with p-halo groups, entries
8−10, Table 2) or negligible (substituted with CN group) yields
were obtained in the case of quinoxaline substrates. We
speculated that such a difference may arise from the different
C−H activation mechanisms between quinoxaline and O-methyl
oxime substrates. The former substrate may involve the
electrophilic aromatic substitution mechanism (SEAr),21 namely
electrophilic metalation.22 In this mechanism, electron-rich
arenes usually undergo C−H functionalization more smoothly;23
the latter substrate may involve in the concerted metalation
deprotonation mechanism (CMD)24 in which electron-deficient
arenes usually undergo C−H functionalization more smoothly
due to enhanced acidity.25 Note that substrates bearing a
methoxy- or nitro-meta-substituted phenyl ring could exclusively
afford a regioisomer in which the nitro group was introduced to
the para-position to the already present substituent (entries, 6, 17,
6f and 6q, Table 4). We speculated that such regioselectivity
was generally governed by the steric effect upon the formation
of the related palladacycle intermediate leading to the cleavage
of the less sterically hindered o-C−H bond (see Scheme 3, vide
infra).25a,26 When substrates other than acetophenone O-methyl
oximes were used, the reaction still proceeded smoothly to give
the desired products in moderate to good yields (55−83%, entries
19−23, Table 4). Besides the excellent regioselectivity, the
present reaction also showed excellent chemoselectivity as most
reactions gave mononitration products predominantly (>95%).
Figure 1. Pd-catalyzed ortho-nitration of aromatic C−H bond in 3
directed by other N-heterocycle directing groups. Conditions: 3
(0.3 mmol), Pd(OAc)2 (0.03 mmol), AgNO2 (0.6 mmol), K2S2O8
(0.6 mmol) in 3.5 mL of DCE at 130 °C for 48 h. aCAN (0.6 mmol) was
used as the oxidant.
sources, oxidants, solvents, and temperatures (Table 3), we finally
found that Pd(OCOCF3)2 (10 mol %) was a better catalyst and
110 °C was a more suitable temperature for the C−H nitration of
5a, in which case the desired product 6a could be obtained in 83%
isolated yield with AgNO2 (2 equiv) as the nitro source, K2S2O8
(2 equiv) as the oxidant, and DCE as the solvent for 48 h (entry 4,
Table 3).
To investigate the scope of the reaction, a variety of aryl ketone
O-methyl oximes 5 were subjected to the optimal reaction
conditions (Table 4). In the participation of electron-rich aryl
rings, the reaction proceeded smoothly to furnish the desired
nitroarenes in moderate to good yields (50−85%, entries 1−8,
Table 4). Surprisingly, when electron-deficient aryl rings were
employed, the reaction proceeded even more cleanly to furnish
the corresponding nitroarenes in moderate to excellent yields
(72−91%, entries 9−18 except 13, Table 4) which was opposite
a
Table 3. Optimization of Reaction Conditions for Ortho-Nitration of 5a
b
entry
catalyst
oxidant
temp (°C)
solvent
DCE
yield (%)
c
1
Pd(OAc)2
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
Cu(OAc)2
PhI(OAc)2
130
110
130
110
90
56 (51 )
2
Pd(OAc)2
DCE
77
64
3
Pd(OCOCF3)2
Pd(OCOCF3)2
Pd(OCOCF3)2
Pd(OCOCF3)2
PdCl2
DCE
c
4
DCE
88 (83 )
5
DCE
67
42
66
15
0
6
60
DCE
7
110
110
110
110
110
110
110
110
110
110
110
110
110
110
DCE
8
Pd(PPh3)2Cl2
Cu(OAc)2
DCE
9
DCE
10
11
12
13
14
15
16
17
18
19
20
--
DCE
0
Pd(OCOCF3)2
Pd(OCOCF3)2
Pd(OCOCF3)2
Pd(OCOCF3)2
Pd(OCOCF3)2
Pd(OCOCF3)2
Pd(OCOCF3)2
Pd(OCOCF3)2
Pd(OCOCF3)2
Pd(OCOCF3)2
MeCN
MeOH
1,4-dioxane
MeNO2
Et2O
30
<5
10
32
7
THF
0
toluene
DMF
DCE
40
0
0
DCE
0
a
Reaction conditions: 5a (0.3 mmol), catalyst (0.03 mmol), AgNO2 (0.06 mmol), K2S2O8 (0.06 mmol) in 3.5 mL of solvent for 48 h unless
b
c
otherwise noted. GC yields using phenanthrene as an internal standard. Isolated yields.
D
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a
Table 4. Pd-Catalyzed Ortho-Nitration of Aryl Ketone O-Methyl Oximes 5
a
Reaction conditions: 5 (0.3 mmol), Pd(OCOCF3)2 (0.03 mmol), AgNO2 (0.6 mmol), K2S2O8 (0.6 mmol) in 3.5 mL of DCE at 110 °C for 48 h.
Isolated yields.
b
E
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a
Table 5. Conversion of 6 to 7 via Removal of the O-Methyl Oximyl Group
a
b
Reaction conditions: 6 (0.2 mmol), aq HCl (12 N, 1.0 mL), CH2Cl2 (1.0 mL) in a sealed tube in 100 °C for 24 h. Isolated yields.
The removal of the O-methyl oximyl directing group in 6 was
readily achieved via treatment of 6 with aq HCl (12 N) in CH2Cl2
at 100 °C for 24 h in a sealed tube according to a modified pro-
cedure reported by Sanford.18a Selected examples of trans-
formation of 6 to 7 were listed in Table 5. Generally, o-nitro aryl
ketones 7 could be selectively obtained in moderate to good
yields (40−98%, entries 1−14, Table 5). Starting from aryl
ketones, we have realized a regiospecific transformation of aryl
ketones to o-nitroaryl ketones via an overall three-step process
involving the Pd-catalyzed chelation-assisted ipso-nitration of
C−H bond as the key step.
Several experiments were done to gain a mechanistic insight
into the Pd-catalyzed C−H nitration. First, a binuclear
palladacycle 8 was prepared from the stoichiometric reaction
of 3a with Pd(OAc)2.27 It was found that 8 was also a suitable
catalyst for the nitration of 3a to give the desired product 4a in
67% GC yield (eq 1, Scheme 1). For acetophenone O-methyl
oxime 5a, we could not get the binuclear palladacycle 9 (eq 2,
Scheme 1). We then prepared mononuclear palladacycle 10 via
a stoichiometric reaction of 5a with Pd(OAc)2 and Ag2O in
TFA according to a previous literature reported by Cheng.28
Employing 10 (10 mol %) as a catalyst, 5a could also give the
target product 6a in 75% yield under otherwise identical
conditions as the optimal (eq 3, Scheme 1).
Then, the kinetic isotope effects (kH/kD) for the C−H nitration
were determined. The intramolecular kH/kD for substrate 1a-d4
1
was 5.3 0.2, based on the H NMR spectroscopic analyses
(eq 1, Scheme 2); the intermolecular kH/kD of 1a to 1a-d5 was
determined to be 4.6 0.2 (eq 2, Scheme 2); and the inter-
molecular kH/kD of 5a to 5a-d5 was 2.3 0.2 (eq 3, Scheme 2).
These results suggested a rate-determining cyclopalladation step.
Finally, with the reaction proceeding, the formation and gradually
consumption of a brown gas, which should be assigned to NO2
gas,29 were observed in the sealed tube. The nitration of 1a under
F
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for substrate 5, a mechanism involving a mononuclear pallada-
cycle species through the PdII/PdIV catalytic cycle is more
likely.28,36
Scheme 1. Studies on the Catalytic Species
CONCLUSION
■
In summary, we have developed a regiospecific synthesis of
nitroarenes via palladium-catalyzed chelation-assisted C−H
nitration. The present protocol has also been successfully
applied in the regiospecific synthesis of o-nitroaryl ketones from
aryl ketones via a three-step process involving directing group
introduction, ortho-nitration of C−H bond, and directing group
removal. The present strategy for the ipso-nitration of C−H bond
has several characteristic advantages including site-regiospecific
nitration of C−H bond free from the effect of the orientation
rules, excellent mononitration selectivity, broad functional group
and substrate tolerance under neutral conditions, and no need for
prefunctionalization of C−H bonds.
EXPERIMENTAL SECTION
■
General Information. Unless otherwise stated, all reagents were
purchased from commercial suppliers and used without purifications. All
solvents for reactions were dried and distilled prior to use according to
standard methods. Melting points are uncorrected. H and 13C NMR
1
the standard conditions gave a decreased yield of 2a (14%) in the
presence of 0.5 equiv of TEMPO and failed to give 2a by using
2 equiv of TEMPO (eq 4, Scheme 2), demonstrating that the
reaction may involve a radical process.30
spectra were recorded on a spectrometer at 25 °C in CDCl3 at 500 and
125 MHz, respectively, with TMS as internal standard. Chemical shifts
(δ) are expressed in ppm and coupling constants J are given in Hz.
The IR spectra were recorded on an FT-IR spectrometer. GC−MS
experiments were performed with EI source, high resolution mass
spectra (HRMS) were obtained on a TOF MS instrument with EI or ESI
source.
On the basis of the mechanistic experiments described above,
a proposed mechanism for the Pd-catalyzed chelation-assisted
C−H nitration was proposed in Scheme 3. For substrates 1 or 3,
the reaction may proceed via a silver-mediated radical mechan-
ism29,31,32 involving a binuclear palladacycle species through
Starting Materials. Starting materials 2-arylquinoxalines (1a−r),37,38
2-arylpyridines (3a−g),39 2-phenylpyrazole 3i,40 and O-methyl oximes
(5a−w)41 were synthesized according to the literature procedures.
27a,33
34,35
the PdII/PdIII
and/or PdII/PdIV
catalytic cycles; while
Scheme 2. Investigation on the Effects of Kinetic Isotope and Radical Scavenger TEMPO
G
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Scheme 3. Proposed Mechanism
Typical Experimental Procedure for Synthesis of Nitroarenes
2 and 4. Compound 1 or 3 (0.3 mmol), Pd(OAc)2 (6.7 mg,
0.03 mmol), AgNO2 (92.3 mg, 0.6 mmol), K2S2O8 (162.0 mg,
0.6 mmol) or CAN (329.0 mg, 0.6 mmol, for 3h, 3i), and anhydrous
DCE (3.5 mL) were sequentially added to a 25-mL Schlenk flask
equipped with a high-vacuum PTFE valve-to-glass seal. Then the flask
was sealed and stirred at 130 °C for 48 h. Upon completion, the resulting
mixture was diluted with CH2Cl2 (10 mL) and filtered through Celite.
After evaporation of the solvent under vacuum, the residue was purified
by column chromatography on silica gel (100−200 mesh) using
cyclohexane−EtOAc as eluent (3:1, V/V) to give desired product 2 or 4.
2-(2-Nitrophenyl)quinoxaline (2a):42
1H), 7.60 (d, J = 2.5 Hz, 1H), 7.29 (dd, J1 = 8.5, J2 = 2.5 Hz, 1H), 3.96
(s, 3H); 13C NMR (CDCl3, 125 MHz) δ 160.8, 150.9, 149.6, 144.5,
141.9, 141.3, 132.9, 130.4, 130.1, 129.5, 129.2, 125.0, 119.2, 110.1, 56.1;
MS (EI, 70 eV) m/z = 281 (100) [M+], 251 (89); HRMS (EI) for
C15H11N3O3 calcd 281.0800, found 281.0786.
2-(2-Methoxy-6-nitrophenyl)quinoxaline (2d):
pale yellow solid (78.5 mg, 93%); mp 144−145 °C; IR (KBr) ν = 1533
(NO2) cm−1; 1H NMR (CDCl3, 500 MHz) δ 8.98 (s, 1H), 8.18−8.16
(m, 1H), 8.06−8.04 (m, 1H), 7.81−7.75 (m, 2H), 7.69 (d, J = 7.5 Hz,
1H), 7.60 (t, J = 8.0 Hz, 1H), 7.30 (d, J = 8.5 Hz, 1H), 3.82 (s, 3H); 13C
NMR (CDCl3, 125 MHz) δ 158.3, 150.4, 149.0, 146.4, 142.2, 141.3,
130.9, 130.09, 130.06, 129.5, 129.3, 122.2, 116.7, 115.7, 56.6; MS (EI,
70 eV) m/z = 281 (42) [M+], 263 (42), 233 (100); HRMS (EI) for
C15H11N3O3 calcd 281.0800, found 281.0817.
pale yellow solid (64.8 mg, 86%); mp 114−115 °C (lit.42 mp 116−
118 °C); IR (KBr) ν = 1531 (NO2) cm−1; 1H NMR (CDCl3, 500 MHz)
δ 8.97 (s, 1H), 8.18−8.10 (m, 3H), 7.83−7.68 (m, 5H); 13C NMR
(CDCl3, 125 MHz) δ 151.1, 148.8, 144.3, 141.8, 141.6, 133.3, 133.0,
131.9, 130.6, 130.4, 130.3, 129.6, 129.3, 125.0; MS (EI, 70 eV) m/z =
251 (83) [M+], 221(100); HRMS (EI) for C14H9N3O2 calcd 251.0695,
found 251.0690.
2-(5-Methoxy-2-nitrophenyl)quinoxaline (2e):
2-(4-Methyl-2-nitrophenyl)quinoxaline (2b):
pale yellow solid (69.2 mg, 82%); mp 178−179 °C; IR (KBr) ν = 1575
(NO2) cm−1; 1H NMR (CDCl3, 500 MHz) δ 8.89 (s, 1H), 8.24 (d, J =
9.0 Hz, 1H), 8.19−8.11 (m, 2H), 7.83−7.81 (m, 2H), 7.13−7.09 (m,
2H), 3.95 (s, 3H); 13C NMR (CDCl3, 125 MHz) δ 163.4, 152.0, 144.7,
141.8, 141.5, 141.1, 136.0, 130.5, 130.3, 129.5, 129.3, 127.7, 117.1, 115.1,
56.2; MS (EI, 70 eV) m/z = 281 (60) [M+], 251 (100); HRMS (EI) for
C15H11N3O3 calcd 281.0800, found 281.0793.
pale yellow solid (60.5 mg, 76%); mp 153−154 °C; IR (KBr) ν = 1531
(NO2) cm−1; 1H NMR (CDCl3, 500 MHz) δ 8.94 (s, 1H), 8.17−8.15
(m, 1H), 8.11−8.09 (m, 1H), 7.92 (s, 1H), 7.82−7.80 (m, 2H), 7.64 (d,
J = 7.5 Hz, 1H), 7.58 (d, J = 7.5, 1H), 2.54 (s, 3H); 13C NMR (CDCl3,
125 MHz) δ 151.1, 148.6, 144.4, 141.9, 141.5, 141.3, 133.9, 131.7, 130.5,
130.3, 130.1, 129.6 129.3 125.3, 21.2 MS (EI, 70 eV) m/z = 265 (79)
[M+], 235 (100); HRMS (EI) for C15H11N3O2 calcd 265.0851, found
265.0851.
3-Nitro-4-(quinoxalin-2-yl)phenol (2f):
2-(4-Methoxy-2-nitrophenyl)quinoxaline (2c):
yellow solid (64.9 mg, 81%); mp 184−185 °C; IR (KBr) ν = 1537
(NO2), 3201 (OH) cm−1; 1H NMR (CDCl3, 500 MHz) δ 10.80 (s, 1H),
9.32 (s, 1H), 8.98 (d, J = 2.5 Hz, 1H), 8.51 (dd, J1 = 8.5 Hz, J2 = 2.5 Hz,
1H), 8.15−8.12 (m, 2H), 7.83−7.77 (m, 2H), 7.36 (d, J = 8.5 Hz, 1H);
13C NMR (CDCl3, 125 MHz) δ 156.3, 148.7, 142.08, 142.04, 141.7,
136.0, 134.0, 130.7, 130.0, 129.5, 129.4, 129.2, 123.9, 121.0; MS (EI,
70 eV) m/z = 267 (100) [M+], 221 (53); HRMS (EI) for C14H9N3O3
calcd 267.0644, found 267.0656.
yellow solid (74.3 mg, 88%); mp 157−158 °C; IR (KBr) ν = 1531
(NO2) cm−1; 1H NMR (CDCl3, 500 MHz) δ 8.92 (s, 1H), 8.16−8.14
(m, 1H), 8.10−8.09 (m, 1H), 7.81−7.79 (m, 2H), 7.68 (d, J = 8.5 Hz,
H
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2-(4-Phenyl-2-nitrophenyl)quinoxaline (2g):
MS (EI, 70 eV) m/z = 309 (3) [M+], 267 (57), 237 (18); HRMS (EI)
for C16H11N3O4 calcd 309.0750, found 309.0753.
2-(3-Nitrothiophene-2-yl)quinoxaline (2n):
yellow solid (85.4 mg, 87%); mp 150−151 °C; IR (KBr) ν = 1537
(NO2) cm−1; 1H NMR (CDCl3, 500 MHz) δ 9.01 (s, 1H), 8.32 (d, J =
1.5 Hz, 1H), 8.19−8.11 (m, 2H), 7.99 (dd, J1 = 8.0 Hz, J2 = 2.0 Hz, 1H),
yellow solid (27.0 mg, 35%); mp 247−248 °C; IR (KBr) ν = 1537
(NO2) cm−1; 1H NMR (CDCl3, 500 MHz) δ 9.29 (s, 1H), 8.15−8.12
(m, 2H), 8.00 (d, J = 4.5 Hz, 1H), 7.86−7.80 (m, 2H), 7.77 (d, J = 4.5
Hz, 1H); 13C NMR (CDCl3, 125 MHz) δ 148.9, 145.2, 142.5, 142.0,
141.1, 131.2, 130.8, 129.6, 129.4, 129.2, 124.9; MS (EI, 70 eV) m/z =
257 (4) [M+]; HRMS (EI) for C12H7N3O2S calcd 257.0259, found
257.0253.
7.84−7.80 (m, 3H), 7.68 (d, J = 8.0 Hz, 2H), 7.55−7.46 (m, 3H); 13
C
NMR (CDCl3, 125 MHz) δ 150.8, 149.2, 144.3, 143.8, 141.9, 141.6,
137.9, 132.3, 131.4, 131.3, 130.6, 130.4, 129.6, 129.3, 129.0, 127.2,
123.4; MS (EI, 70 eV) m/z = 327 (92), 297 (100); HRMS (EI) for
C20H13N3O2 calcd 327.1008, found 327.1017.
6,7-Dimethyl-2-(4-methyl-2-nitrophenyl)quinoxaline (2p):
2-(4-Fluoro-2-nitrophenyl)quinoxaline (2h):
pale yellow solid (40.5 mg, 46%); mp 189−190 °C; IR (KBr) ν = 1529
(NO2) cm−1; 1H NMR (CDCl3, 500 MHz) δ 8.84 (s, 1H), 7.88 (d, J =
8.0 Hz, 2H), 7.84 (s, 1H), 7.63 (d, J = 8.0 Hz, 1H), 7.56 (d, J = 7.5 Hz,
1H), 2.54 (s, 3H), 2.53 (s, 3H), 2.51 (s, 3H); 13C NMR (CDCl3, 125
MHz) δ 150.0, 148.9, 143.3, 141.3, 141.1, 141.0, 140.9, 140.5, 133.7,
131.6, 130.4, 128.6, 128.3, 125.3, 21.2, 20.5, 20.4; MS (EI, 70 eV) m/z =
293 (78) [M+], 263 (100); HRMS (EI) for C17H15N3O2 calcd 293.1164,
found 293.1180.
pale yellow solid (28.3 mg, 35%); mp 147−148 °C; IR (KBr) ν = 1540
(NO2) cm−1; 1H NMR (CDCl3, 500 MHz) δ 8.94 (s, 1H), 8.19−8.17
(m, 1H), 8.11−8.09 (m, 1H), 7.89−7.76 (m, 4H), 7.54−7.50 (m, 1H);
13C NMR (CDCl3, 125 MHz) δ 162.6 (d, J = 253.8 Hz), 150.1, 149.4 (d,
J = 8.8 Hz), 144.1, 141.8, 141.6, 133.6 (d, J = 8.8 Hz), 130.7, 130.6,
129.6, 129.3, 129.2, 120.6 (d, J = 21.3 Hz), 112.9 (d, J = 27.5 Hz); MS
(EI, 70 eV) m/z = 269 (78) [M+], 239 (100); HRMS (EI) for
C14H8FN3O2 calcd 269.0601, found 269.0605.
2,3-Bis(2-nitrophenyl)quinoxaline (2q):
2-(4-Chloro-2-nitrophenyl)quinoxaline (2i):43
yellow solid (37.7 mg, 44%); mp 193−194 °C; IR (KBr) ν = 1527
(NO2) cm−1; 1H NMR (CDCl3, 500 MHz) δ 8.95 (s, 1H), 8.19−8.17
(m, 1H), 8.11−8.09 (m, 2H), 7.85−7.81 (m, 2H), 7.78−7.72 (m, 2H);
13C NMR (CDCl3, 125 MHz) δ 149.9, 149.2, 144.0, 141.8, 141.7, 136.4,
133.3, 132.9, 131.3, 130.8, 130.7, 129.6, 129.3, 125.2; MS (EI, 70 eV)
m/z = 285.0 (88) [M+], 255.0 (100); HRMS (EI) for C14H8ClN3O2
calcd 285.0305, found 285.0309.
yellow solid (67.0 mg, 60%); mp 207−208 °C; IR (KBr) ν = 1528
(NO2) cm−1; 1H NMR (CDCl3, 500 MHz) δ 8.18 (dd, J1 = 6.5 Hz, J2 =
3.5 Hz, 2H), 7.95 (dd, J1 = 8.5 Hz, J2 = 1.0 Hz, 2H), 7.86 (dd, J1 = 6.5 Hz,
J2 = 3.5 Hz, 2H), 7.68−7.60 (m, 4H), 7.54−7.51 (m, 2H); 13C NMR
(CDCl3, 125 MHz) δ 151.1, 147.7, 141.0, 134.0, 133.4, 132.8, 130.7,
130.1, 129.3, 124.3; MS (EI, 70 eV) m/z = 372 (48) [M+], 342 (59);
HRMS (EI) for C20H12N4O4 calcd 372.0859, found 372.0876.
6,7-Dimethyl-2,3-bis(2-nitrophenyl)quinoxaline (2r):
2-(4-Bromo-2-nitrophenyl)quinoxaline (2j):
white solid (49.5 mg, 50%); mp 193−194 °C; IR (KBr) ν = 1531 (NO2)
cm−1; 1H NMR (CDCl3, 500 MHz) δ 8.95 (s, 1H), 8.26 (d, J = 2.0 Hz,
1H), 8.19−8.17m, 1H), 8.11−8.09 (m, 1H), 7.93 (dd, J1 = 8.0 Hz, J2 =
2.0 Hz, 1H), 7.85−7.83 (m, 2H), 7.66 (d, J = 8.5 Hz, 1H); 13C NMR
(CDCl3, 125 MHz) δ 149.9, 149.1, 143.8, 141.8, 141.6 136.3 133.1,
131.6, 130.8, 130.7, 129.6, 129.3, 128.0, 123.9; MS (EI, 70 eV) m/z =
331 (91) [M+], 301 (63), 220 (100); HRMS (EI) for C14H8BrN3O2
calcd 328.9800, found 328.9803.
yellow solid (66.1 mg, 55%); mp 211−212 °C; IR (KBr) ν = 1528
(NO2) cm−1; 1H NMR (CDCl3, 500 MHz) δ 7.94−7.91 (m, 4H), 7.64−
7.57 (m, 4H), 7.52 −7.48 (m, 2H), 2.54 (s, 6H); 13C NMR (CDCl3, 125
MHz) δ 149.8, 147.9, 141.4, 140.0, 133.8, 133.7, 132.7, 129.8, 128.3,
124.3, 20.4; MS (EI, 70 eV) m/z = 400 (41) [M+], 370 (7); HRMS (EI)
for C22H16N4O4 calcd 400.1172, found 400.1174.
2-(2-Nitrophenyl)pyridine (4a):44
3-Nitro-2-(quinoxalin-2-yl)phenyl acetate (2l):
orange oil (25.2 mg, 42%); IR (neat) ν = 1524 (NO2) cm−1; 1H NMR
(CDCl3, 500 MHz) δ 8.65 (d, J = 4.5 Hz, 1H), 7.89 (d, J = 8.0 Hz, 1H),
7.81−7.78 (m, 1H), 7.68−7.47 (m, 4H), 7.33−7.30 (m, 1H); 13C NMR
(CDCl3, 125 MHz) δ 155.4, 149.6, 149.3, 136.8, 135.2, 132.3, 131.2,
129.2, 124.3, 122.9, 122.6; MS (EI, 70 eV) m/z = 200 (20) [M+], 170
(100); HRMS (EI) for C11H8N2O2 calcd 200.0586, found 200.0591.
yellow solid (47.3 mg, 51%); mp 106−107 °C; IR (KBr) ν = 1531
1
(NO2), 1774 (CO) cm−1; H NMR (CDCl3, 500 MHz) δ 8.91 (s,
1H), 8.20−8.18 (m, 1H), 8.10−8.07 (m, 2H), 7.87−7.80 (m, 2H), 7.70
(t, J = 8.5, 1H), 7.58 (dd, J1 = 8.5 Hz, J1 = 1.0 Hz, 1H), 1.99 (s, 3H); 13
C
NMR (CDCl3, 125 MHz) δ 168.4, 149.74, 149.69, 147.9, 145.0, 142.0,
141.4, 130.6, 130.53, 130.51, 129.5, 129.3, 128.4, 126.7, 122.5, 20.4;
I
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2-(2-Methyl-6-nitrophenyl)pyridine (4b):
2-(1-Nitronaphthalen-2-yl)pyridine and 2-(3-nitronaphthalen-2-
yl)pyridine (4g + 4g′):
brown oil (20.6 mg, 32%); IR (neat) ν = 1527 (NO2) cm−1; 1H NMR
(CDCl3, 500 MHz) δ 8.69 (d, J = 4.5 Hz, 1H), 7.84 (d, J = 8.0 Hz, 1H),
7.81−7.77 (m, 1H), 7.53 (d, J = 7.5 Hz, 1H), 7.44 (t, J = 8.0 Hz, 1H),
7.33−7.30 (m, 2H), 2.18 (s, 3H); 13C NMR (CDCl3, 125 MHz) δ 155.6,
149.8, 149.5, 139.1, 136.5, 134.9, 134.8, 128.6, 123.9, 122.6, 121.9, 20.1;
MS (EI, 70 eV) m/z = 213 (100) [M+], 167 (81); HRMS (EI) for
C12H9N2O2 (M − H)+ calcd 213.0664, found 213.0668.
yellow oil (33.8 mg, 45%); 1H NMR (CDCl3, 500 MHz) δ 8.74 (d, J =
5 Hz, 1H), 8.69 (d, J = 4.5 Hz, 1H), 8.47 (s, 1H), 8.09−7.60 (m, 14H),
7.55−7.53 (m, 1H), 7.36−7.32 (m, 2H).
2-(1-Nitronaphthalen-2-yl)pyridine (4g, recrystallization from
mixture of 4g and 4g′):
2-(4-Fluoro-2-nitrophenyl)pyridine (4c):
pale yellow solid (36.7 mg, 56%); mp 104−105 °C; IR (KBr) ν = 1539
(NO2) cm−1; 1H NMR (CDCl3, 500 MHz) δ 8.64 (d, J = 4.5 Hz, 1H),
7.82−7.78 (m, 1H), 7.65−7.61 (m, 2H), 7.45 (d, J = 8.0 Hz, 1H), 7.41−
7.31 (m, 2H); 13C NMR (CDCl3, 125 MHz) δ 161.9 (d, J = 252.5 Hz),
154.5, 149.7, 137.0, 132.9 (d, J = 8.8 Hz), 131.52, 131.49, 123.1, 122.7,
119.6 (d, J = 21.3 Hz), 112.3 (d, J = 26.3 Hz); MS (EI, 70 eV) m/z = 218
(32) [M+], 188 (100); HRMS (EI) for C11H7FN2O2 calcd 218.0492,
found 218.0486.
colorless solid (9.5 mg, recrystallization yield 56%); mp 149−150 °C; IR
(KBr) ν = 1534 (NO2) cm−1; 1H NMR (CDCl3, 500 MHz) δ 8.73 (d, J =
1.0 Hz, 1H), 8.07 (d, J = 8.5 Hz, 1H), 7.96 (d, J = 7.5 Hz, 1H), 7.88 (d,
J = 8.5 Hz, 1H), 7.84−7.79 (m, 1H), 7.73 (d, J = 7.5 Hz, 1H), 7.70−7.62
(m, 3H), 7.36−7.33 (m, 1H); 13C NMR (CDCl3, 125 MHz) δ 154.5,
150.0, 147.0, 137.1, 133.6, 130.8, 129.9, 128.9, 128.0, 127.8, 126.3, 124.8,
123.2, 123.0, 122.2; MS (EI, 70 eV) m/z = 250 (42) [M+], 220 (100);
HRMS (EI) for C15H10N2O2 calcd 250.0742, found 250.0742.
10-Nitrobenzo[h]quinoline (4h):46
2-(4-Chloro-2-nitrophenyl)pyridine (4d):45
pale yellow solid (36.6 mg, 52%); mp 106−107 °C; IR (KBr) ν = 1531
(NO2) cm−1; 1H NMR (CDCl3, 500 MHz) δ 8.65 (d, J = 4.5 Hz, 1H),
7.89 (d, J = 2.0 Hz, 1H), 7.82−7.79 (m, 1H), 7.64 (dd, J1 = 8.5 Hz, J2 =
2.0 Hz, 1H), 7.58 (d, J = 8.5 Hz, 1H), 7.46 (d, J = 7.5 Hz, 1H), 7.34−7.32
(m, 1H); 13C NMR (CDCl3, 125 MHz) δ 154.3, 149.8, 149.5, 137.0,
135.0, 133.6 132.4, 132.3, 124.6, 123.2, 122.6; MS (EI, 70 eV) m/z = 234
(27) [M+], 204 (100); HRMS (EI) for C11H7ClN2O2 calcd 234.0196,
found 234.0189.
pale yellow solid (41.0 mg, 61%); mp 158−159 °C (lit.46 168−169); IR
(KBr) ν = 1528 (NO2) cm−1; 1H NMR (CDCl3, 500 MHz) δ 8.92 (dd,
J1 = 4.3 Hz, J2 = 1.7 Hz, 1H), 8.19 (dd, J1 = 8.1 Hz, J1 = 1.7 Hz, 1H), 8.04
(dd, J1 = 7.7 Hz, J2 = 1.5 Hz, 1H), 7.85−7.68 (m, 4H), 7.55 (dd, J1 =
8.1 Hz, J2 = 4.4 Hz, 1H); 13C NMR (CDCl3, 125 MHz) δ 148.8, 143.4,
137.5, 136.7, 134.9, 130.4, 127.4, 127.3, 127.2, 127.0, 122.8, 121.7,
121.4; MS (EI, 70 eV) m/z = 224 (47) [M+], 194 (25); HRMS (EI) for
C13H8N2O2 calcd 224.0586, found 224.0592.
2-(5-Chloro-2-nitrophenyl)pyridine (4e):
1-(2-Nitrophenyl)-1H-pyrazole (4i):47
1
pale yellow oil (26.7 mg, 38%); IR (neat) ν = 1529 (NO2) cm−1; H
pale yellow solid (31.2 mg, 55%); mp 87−88 °C (lit.47 mp 87−88 °C);
IR (KBr) ν = 1535 (NO2) cm−1; 1H NMR (CDCl3, 500 MHz) δ 7.87
(dd, J1 = 8.0 Hz, J2 = 1.0 Hz, 1H), 7.75 (d, J = 1.5 Hz, 1H), 7.72 (d, J =
2.5 Hz, 1H), 7.70−7.68 (m, 1H), 7.59 (dd, J1 = 8.0 Hz, J2 = 1.0 Hz, 1H),
7.54−7.50 (m, 1H), 6.50 (t, J = 2.0 Hz, 1H); 13C NMR (CDCl3,
125 MHz) δ 144.7, 142.3, 133.5, 133.0, 129.7, 128.3, 126.3, 125.0, 108.2;
MS (EI, 70 eV) m/z = 189 (100) [M+], 143 (35); HRMS (EI) for
C9H7N3O2 calcd 189.0538, found 189.0543.
NMR (CDCl3, 500 MHz) δ 8.67 (d, J = 4.5 Hz, 1H), 7.89 (d, J = 9.0 Hz,
1H), 7.84−7.80 (m, 1H), 7.62 (d, J = 2.5 Hz, 1H), 7.52 (dd, J1 = 9.0 Hz,
J2 = 2.0 Hz, 1H), 7.47 (d, J = 8.0 Hz, 1H), 7.37−7.34 (m, 1H); 13C NMR
(CDCl3, 125 MHz) δ 154.3, 149.8, 147.4, 138.6, 137.0, 136.9, 131.3,
129.1, 125.8, 123.3, 122.7; MS (EI, 70 eV) m/z = 234 (17) [M+], 204
(100); HRMS (EI) for C11H7ClN2O2 calcd 234.0196, found 234.0200.
2-(4-Bromo-2-nitrophenyl)pyridine (4f):
General Procedure for the Synthesis of o-Nitro Aryl Ketone
O-Methyl Oximes 6. Aryl ketone O-methyl oximes 5 (0.3 mmol),
Pd(OCOCF3)2 (10 mg, 0.03 mmol), AgNO2 (92.3 mg, 0.6 mmol),
K2S2O8 (162.0 mg, 0.6 mmol), and anhydrous DCE (3.5 mL) were
sequentially added to a 25-mL Schlenk flask equipped with a high-
vacuum PTFE valve-to-glass seal. Then the flask was sealed and stirred
at 110 °C for 48 h. Upon completion, the reaction mixture was cooled
to rt and diluted with CH2Cl2 (10 mL) and filtered through Celite.
The solvent was then removed under reduce pressure and the residue
was purified by flash column chromatography on silica gel with cyclo-
hexane−EtOAc (3:1, V/V) as the eluent.
yellow oil (47.7 mg, 57%); IR (neat) ν = 1534 (NO2) cm−1; 1H NMR
(CDCl3, 500 MHz) δ 8.65−8.64 (m, 1H), 8.03 (d, J = 2.0 Hz, 1H),
7.82−7.78 (m, 2H), 7.51 (d, J = 8.5 Hz, 1H), 7.46 (d, J = 7.5 Hz, 1H),
7.34−7.32 (m, 1H); 13C NMR (CDCl3, 125 MHz) δ 154.4 149.8, 149.6,
137.0, 135.4, 134.0, 132.5, 127.4, 123.2, 122.6, 122.5; MS (EI, 70 eV)
m/z = 278 (18) [M+], 248 (43), 169 (100); HRMS (EI) for
C11H7BrN2O2 calcd 277.9691, found 277.9692.
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(E)-1-(2-Nitrophenyl)ethanone O-methyl oxime (6a):48
white solid (47.8 mg, 71%); mp 58−59 °C; IR (KBr) ν = 1508 (NO2)
cm−1; 1H NMR (CDCl3, 500 MHz) δ 8.13 (d, J = 9.5 Hz, 1H), 6.97 (dd,
J1 = 9.0 Hz, J2 = 3.0 Hz, 1H), 6.87 (d, J = 3.0 Hz, 1H), 3.98 (s, 3H), 3.92
(s, 3H), 2.16 (s, 3H); 13C NMR (CDCl3, 125 MHz) δ 163.5, 155.2,
140.5, 136.1, 127.4, 115.8, 114.4, 62.0, 56.1, 16.3; MS (EI, 70 eV) m/z =
224 (91) [M+], 179 (76); HRMS (EI) for C10H12N2O4 calcd 224.0797,
found 224.0801.
yellow oil (48.4 mg, 83%); IR (neat) ν = 1527 (NO2) cm−1; 1H NMR
(CDCl3, 500 MHz) δ 8.01 (dd, J1 = 8.0 Hz, J2 = 1.0 Hz, 1H), 7.66−7.63
(m, 1H), 7.55−7.52 (m, 1H), 7.47 (dd, J1 = 7.5 Hz, J2 = 1.5 Hz, 1H), 3.98
(s, 3H), 2.18 (s, 3H); 13C NMR (CDCl3, 125 MHz) δ 154.1, 148.0,
133.24, 133.16, 130.6, 129.5, 124.6, 62.0, 15.9; MS (EI, 70 eV) m/z =
194 (31) [M+], 149 (44); HRMS (EI) for C9H10N2O3 calcd 194.0691,
found 194.0685.
(E)-1-(4-Benzyloxy-2-nitrophenyl)ethanone O-methyl oxime (6g):
yellow oil (45.0 mg, 50%); IR (neat) ν = 1538 (NO2) cm−1; 1H NMR
(CDCl3, 500 MHz) δ 7.60 (d, J = 2.5 Hz, 1H), 7.44−7.36 (m, 6H), 7.21
(dd, J1 = 8.5 Hz, J2 = 2.5 Hz, 1H), 5.16 (s, 2H), 3.96 (s, 3H), 2.14 (s,
3H); 13C NMR (CDCl3, 125 MHz) δ 159.2 154.0, 148.7, 135.6, 131.6,
128.8, 128.5, 127.5, 125.8, 120.1, 110.7, 70.8, 61.9, 16.0; MS (EI, 70 eV)
m/z = 300 (13) [M+], 91(100); HRMS (EI) for C16H16N2O4 calcd
300.1110, found 300.1113.
(E)-1-(4-Methyl-2-nitrophenyl)ethanone O-methyl oxime (6b):
white solid (43.7 mg, 70%); mp 45−46 °C; IR (KBr) ν = 1525 (NO2)
cm−1; 1H NMR (CDCl3, 500 MHz) δ 7.82 (s, 1H), 7.44 (d, J = 8.5 Hz),
7.34 (d, J = 8.5 Hz,1H), 3.96 (s, 3H), 2.46 (s, 3H), 2.15 (s, 3H); 13C
NMR (CDCl3, 125 MHz) δ 154.1, 147.9, 140.2, 133.8, 130.4, 128.4,
124.9, 62.0, 21.0, 15.9; MS (EI, 70 eV) m/z = 208 (43) [M+], 163 (51);
HRMS (EI) for C10H12N2O3 calcd 208.0848, found 208.0845.
(E)-1-(4,6-Dimethyl- 2-nitrophenyl)ethanone O-methyl oxime
(6h):
(E)-1-(6-Methyl-2-nitrophenyl)ethanone O-methyl oxime (6c):
brown oil (48.0 mg, 72%); IR (neat) ν = 1532 (NO2) cm−1; 1H NMR
(CDCl3, 500 MHz) δ 7.68 (s, 1H), 7.31 (s, 1H), 3.92 (s, 3H), 2.41 (s,
3H), 2.32 (s, 3H), 2.20 (s, 3H); 13C NMR (CDCl3, 125 MHz) δ 154.0,
148.8, 139.2, 138.7, 135.9, 129.6, 122.4, 61.8, 20.9, 19.4, 16.5; MS (EI,
70 eV) m/z = 222 (57) [M+], 177 (42); HRMS (EI) for C11H14N2O3
calcd 222.1004, found 222.1008
yellow oil (46.8 mg, 75%); IR (neat) ν = 1531 (NO2) cm−1; 1H NMR
(CDCl3, 500 MHz) δ 7.87 (d, J = 8.0 Hz, 1H), 7.50 (d, J = 7.5 Hz, 1H),
7.40 (t, J = 8.0 Hz, 1H), 3.93 (s, 3H), 2.37 (s, 3H), 2.23 (s, 3H); 13C
NMR (CDCl3, 125 MHz) δ 153.9, 148.8, 139.1, 135.2, 132.2, 128.8,
122.0, 61.9, 19.4, 16.4; MS (EI, 70 eV) m/z = 208 (68) [M+], 163 (40);
HRMS (EI) for C10H12N2O3 calcd 208.0848, found 208.0850.
(E)-1-(4-Fluoro-2-nitrophenyl)ethanone O-methyl oxime (6i):
(E)-1-(4-Methoxy-2-nitrophenyl)ethanone O-methyl oxime (6d):
brown oil (52.8 mg, 83%); IR (neat) ν = 1540 (NO2) cm−1; 1H NMR
(CDCl3, 500 MHz) δ 7.73 (dd, J1 = 8.0 Hz, J2 = 2.5 Hz, 1H), 7.47 (dd,
J1 = 8.5 Hz, J2 = 5.5 Hz, 1H), 7.39−7.35 (m, 1H), 3.97 (s, 3H), 2.16 (s,
3H); 13C NMR (CDCl3, 125 MHz) δ 162.0 (d, 1JF−C = 251.3 Hz), 153.2,
3
4
148.7, 132.3 (d, JF−C = 8.8 Hz), 129.4 (d, JF−C = 3.8 Hz), 120.4 (d,
2JF−C = 21.3 Hz), 112.3 (d, 2JF−C = 26.3 Hz), 62.1, 15.9; MS (EI, 70 eV)
m/z = 212 (48) [M+], 167 (59); HRMS (EI) for C9H9FN2O3 calcd
212.0597, found 212.0591.
white solid (48.4 mg, 72%); mp 54−55 °C; IR (KBr) ν = 1534 (NO2)
cm−1; 1H NMR (CDCl3, 500 MHz) δ 7.50 (d, J = 2.5 Hz, 1H), 7.36 (d,
J = 8.5 Hz, 1H), 7.15 (dd, J1 = 8.5 Hz, J2 = 2.5 Hz,1H), 3.95 (s, 3H), 3.89
(s, 3H), 2.13 (s, 3H); 13C NMR (CDCl3, 125 MHz) δ 160.1, 153.8,
148.7, 131.5, 125.5, 119.3, 109.5, 61.9, 56.0, 16.0; MS (EI, 70 eV) m/z =
224 (88) [M+], 179 (61); HRMS (EI) for C10H12N2O4 calcd 224.0797,
found 224.0792.
(E)-1-(4-Chloro-2-nitrophenyl)ethanone O-methyl oxime (6j):
(E)-1-(6-Methoxy-2-nitrophenyl)ethanone O-methyl oxime (6e):
1
pale yellow oil (56.2 mg, 82%); IR (neat) ν = 1536 (NO2) cm−1; H
NMR (CDCl3, 500 MHz) δ 7.98 (d, J = 1.5 Hz, 1H), 7.61 (dd, J1 =
8.5 Hz, J2 = 2.0 Hz, 1H), 7.42 (d, J = 8.5 Hz, 1H), 3.96 (s, 3H), 2.15 (s,
3H); 13C NMR (CDCl3, 125 MHz) δ 153.0, 148.5, 135.4, 133.2, 131.7,
131.5, 124.8, 62.2, 15.7; MS (EI, 70 eV) m/z = 228 (43) [M+], 183 (71);
HRMS (EI) for C9H9ClN2O3 calcd 228.0302, found 228.0305.
(E)-1-(6-Chloro-2-nitrophenyl)ethanone O-methyl oxime (6k):
white solid (57.2 mg, 85%); mp 74−75 °C; IR (KBr) ν = 1525 (NO2)
cm−1; 1H NMR (CDCl3, 500 MHz) δ 7.52 (dd, J1 = 8.5 Hz, J2 = 1.0 Hz,
1H), 7.45 (t, J = 8.5 Hz, 1H), 7.16 (dd, J1 = 8.0 Hz, J2 = 0.5 Hz,1H),
3.895 (s, 3H), 3.893 (s, 3H), 2.23 (s, 3H); 13C NMR (CDCl3, 125 MHz)
δ 158.5, 152.2, 149.8, 129.9, 122.0, 115.9, 115.3, 61.8, 56.4, 16.0; MS (EI,
70 eV) m/z = 224 (31) [M+], 178 (100); HRMS (EI) for C10H12N2O4
calcd 224.0797, found 224.0795.
(E)-1-(5-Methoxy-2-nitrophenyl)ethanone O-methyl oxime (6f):
white solid (58.3 mg, 85%); mp 57−58 °C; IR (KBr) ν = 1534 (NO2)
cm−1; 1H NMR (CDCl3, 500 MHz) δ 7.91(dd, J1 = 8.0 Hz, J2 = 1.5 Hz,
1H), 7.69 (dd, J1 = 8.0 Hz, J2 = 1.0 Hz, 1H), 7.48 (t, J = 8.0 Hz, 1H), 3.93
(s, 3H), 2.28 (s, 3H), 13C NMR (CDCl3, 125 MHz) δ 152.4, 150.0,
135.6, 134.3, 131.9, 129.8, 122.7, 62.2, 16.1; MS (EI, 70 eV) m/z = 228
K
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(28) [M+], 183 (75); HRMS (EI) for C9H9ClN2O3 calcd 228.0302,
found 228.0307.
(E)-1-(4-Bromo-2-nitrophenyl)ethanone O-methyl oxime (6l):
white solid (58.1 mg, 81%); mp 102−104 °C; IR (KBr) ν = 1534 (NO2)
cm−1; 1H NMR (CDCl3, 500 MHz) δ 8.37−8.35 (m, 2H), 8.07 (d, J =
9.5 Hz, 1H), 4.00 (s, 3H), 2.21 (s, 3H); 13C NMR (CDCl3, 125 MHz) δ
151.42, 151.37, 149.4, 134.3, 125.8, 125.7, 124.4, 62.5, 15.2; MS (EI,
70 eV) m/z = 239 (43) [M+], 194 (76); HRMS (EI) for C9H9N3O5
calcd 239.0542, found 239.0539.
(E)-1-(4-Methylsulfonyl-2-nitrophenyl)ethanone O-methyl oxime
(6r):
pale yellow solid (63.1 mg, 77%); mp 77−78 °C; IR (KBr) ν = 1534
(NO2) cm−1; 1H NMR (CDCl3, 500 MHz) δ 8.12 (d, J = 2.0 Hz, 1H),
7.77 (dd, J1 = 8.0 Hz, J2 = 2.0 Hz, 1H), 7.36 (d, J = 8.5 Hz, 1H), 3.97 (s,
3H), 2.15 (s, 3H); 13C NMR (CDCl3, 125 MHz) δ 153.0, 148.5, 136.1,
131.94, 131.88, 127.6, 122.8, 62.2, 15.7; MS (EI, 70 eV) m/z = 272 (19)
[M+], 227 (41); HRMS (EI) for C9H9BrN2O3 calcd 271.9797, found
271.9807.
white solid (74.3 mg, 91%); mp 123−124 °C; IR (KBr) ν = 1533 (NO2)
cm−1; 1H NMR (CDCl3, 500 MHz) δ 8.50 (d, J = 1.5 Hz, 1H), 8.19 (dd,
J1 = 8.0 Hz, J2 = 1.5 Hz, 1H), 7.72 (d, J = 8.0 Hz, 1H), 3.98 (s, 3H), 3.13
(s, 3H), 2.19 (s, 3H); 13C NMR (CDCl3, 125 MHz) δ 152.2, 148.5,
142.0, 137.7, 132.1, 131.3, 123.9, 62.4, 44.3, 15.4; MS (EI, 70 eV) m/z =
272 (42) [M+], 227 (89); HRMS (EI) for C10H12N2O5S calcd 272.0467,
found 272.0461.
(E)-1-(6-Bromo-2-nitrophenyl)ethanone O-methyl oxime (6m):
(E)-1-(2-Nitrophenyl)propionyl O-methyl oxime (6s):
yellow solid (34.4 mg, 42%); mp 62−63 °C; IR (KBr) ν = 1534 (NO2)
cm−1; 1H NMR (CDCl3, 500 MHz) δ 7.97 (d, J = 8.0 Hz, 1H), 7.88 (d,
J = 8.0 Hz, 1H), 7.40 (t, J = 8.0 Hz, 1H), 3.93 (s, 3H), 2.29 (s, 3H); 13C
NMR (CDCl3, 125 MHz) δ 153.7, 150.0, 137.5, 133.6, 130.0, 124.8,
123.3, 62.1, 16.2; MS (EI, 70 eV) m/z = 272 (12) [M+], 212 (56);
HRMS (EI) for C9H9BrN2O3 calcd 271.9797, found 271.9802.
(E)-1-(4-Iodo-2-nitrophenyl)ethanone O-methyl oxime (6n):
yellow oil (51.8 mg, 83%); IR (neat) ν = 1534 (NO2) cm−1; 1H NMR
(CDCl3,500 MHz) δ 8.05 (dd, J1 = 8.5 Hz, J2 = 1.0 Hz, 1H), 7.67 (dd,
J1 = 7.5 Hz, J2 = 1.0 Hz, 1H), 7.64−7.42 (m, 2H), 3.94 (s, 3H), 2.72 (q,
J = 7.5 Hz, 2H), 1.02 (t, J = 7.5 Hz, 3H); 13C NMR (CDCl3, 125 MHz) δ
159.4, 148.2, 133.1, 132.0, 131.1, 129.4, 124.6, 62.0, 22.9, 10.1; MS (EI,
70 eV) m/z = 208 (20) [M+], 163 (12); HRMS (EI) for C10H12N2O3
calcd 208.0848, found 208.0844.
(E)-1-(4-Bromo-2-nitrophenyl)valeryl O-methyl oxime (6t):
white solid (76.8 mg, 80%); mp 72−73 °C; IR (KBr) ν = 1524 (NO2)
cm−1; 1H NMR (CDCl3, 500 MHz) δ 8.30 (d, J = 2.0 Hz, 1H), 7.96 (dd,
J1 = 8.0 Hz, J2 = 1.5 Hz, 1H), 7.20 (d, J = 3.0 Hz, 1H), 3.96 (s, 3H), 2.14
(s, 3H), 13C NMR (CDCl3, 125 MHz) δ 153.1, 148.3, 142.1, 133.2,
132.5, 131.8, 93.3, 62.2, 15.6; MS (EI, 70 eV) m/z = 320 (100) [M+],
275 (71); HRMS (EI) for C9H9IN2O3 calcd 319.9658, found 319.9654.
(E)-1-(4-Cyano-2-nitrophenyl)ethanone O-methyl oxime (6o):
brown oil (64.3 mg, 68%); IR (neat) ν = 1537 (NO2) cm−1; 1H NMR
(CDCl3, 500 MHz) δ 8.16 (d, J = 2.0 Hz, 1H), 7.77 (dd, J1 = 8.5 Hz, J2 =
2.0 Hz, 1H), 7.31 (d, J = 8.0 Hz, 1H), 3.93 (s, 3H), 2.64 (t, J = 7.5 Hz,
2H), 1.40−1.32 (m, 4H), 0.88 (t, J = 7.5 Hz, 3H); 13C NMR (CDCl3,
125 MHz) δ 157.3, 148.7, 136.0, 132.2, 131.2, 127.7, 122.7, 61.2, 29.1,
27.8, 22.9, 13.7; MS (EI, 70 eV) m/z = 315(10) [M+], 270 (70); HRMS
(EI) for C12H15BrN2O3 calcd 314.0266, found 314.0270.
white solid (59.2 mg, 90%); mp 76−77 °C; IR (KBr) ν = 1533 (NO2)
cm−1; 1H NMR (CDCl3, 500 MHz) δ 8.24 (d, J = 1.5 Hz, 1H), 7.91 (dd, J1
= 8.0 Hz, J2 = 1.5 Hz, 1H), 7.64 (d, J = 8.0 Hz, 1H), 3.98 (s, 3H), 2.17 (s,
3H); 13C NMR (CDCl3, 125 MHz) δ 152.1, 148.4, 137.0, 136.0, 131.8,
128.1, 116.2, 113.7, 62.5, 15.; MS (EI, 70 eV) m/z = 219 (14) [M+], 174
(25); HRMS (EI) for C10H9N3O3 calcd 219.0644, found 219.0638.
(E)-1-(2,4-Binitrophenyl)ethanone O-methyl oxime (6p):
(E)- (2-Nitrophenyl)phenyl methanone O-methyl oxime (6u):
yellow oil (63.8 mg, 83%); IR (neat) ν = 1530 (NO2) cm−1; 1H NMR
(CDCl3, 500 MHz) δ 7.97 (dd, J1 = 8.0 Hz, J2 = 1.0 Hz, 1H), 7.67 (dd,
J1 = 7.5 Hz, J2 = 1.0 Hz, 1H), 7.65−7.51 (m, 4H), 7.38−7.37 (m, 2H),
4.01 (s, 3H); 13C NMR (CDCl3, 125 MHz) δ 153.2, 149.2, 132.7, 132.4,
132.2, 131.7, 129.8, 129.72, 129.68, 128.0, 124.5, 62.7; MS (EI, 70 eV)
m/z = 256 (94) [M+], 211 (14); HRMS (EI) for C14H12N2O3 calcd
256.0848, found 256.0843.
white solid (51.7 mg, 72%); mp 65−66 °C; IR (KBr) ν = 1534 (NO2)
cm−1; 1H NMR (CDCl3, 500 MHz) δ 8.80 (d, J = 2.0 Hz, 1H), 8.47 (dd,
J1 = 8.5 Hz, J2 = 2.0 Hz, 1H), 7.72 (d, J = 8.5 Hz, 1H), 4.00 (s, 3H), 2.20
(s, 3H); 13C NMR (CDCl3, 125 MHz) δ 151.9, 148.4, 147.7, 138.4,
132.0, 127.1, 120.0, 62.5, 15.4; MS (EI, 70 eV) m/z = 239 (14) [M+],
194 (31); HRMS (EI) for C9H9N3O5 calcd 239.0542, found 239.0544.
(E)-1-(5-Nitro-2-nitrophenyl)ethanone O-methyl oxime (6q):
(E)-8-Nitro-3,4-dihydro-1(2H)naphthalenone O-methyl oxime
(6v):
yellow solid (36.3 mg, 55%); mp 73−74 °C; IR (KBr) ν = 1536 (NO2)
cm−1; 1H NMR (CDCl3, 500 MHz) δ 7.35−7.30 (m, 3H), 3.92 (s, 3H),
2.78−2.75 (m, 4H), 1.90−1.85 (m, 2H); 13C NMR (CDCl3, 125 MHz)
δ 149.8, 149.1, 142.8, 130.6, 128.4, 123.2, 121.7, 62.3, 30.2, 24.2, 20.7;
L
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MS (EI, 70 eV) m/z = 220 (16) [M+], 159 (100); HRMS (EI) for
C11H12N2O3 calcd 220.0848, found 220.0851.
(E)-5-Nitro-2,3-dihydro-4H-1-benzopyran-4-one O-methyl oxime
(6w):
125 MHz) δ 200.0, 164.4, 141.3, 138.2, 127.0, 114.9, 111.9, 56.2, 30.3;
MS (EI, 70 eV) m/z = 195(38) [M+], 180(100); HRMS (EI) for
C9H9NO4 calcd 195.0532, found 195.0528.
1-(4-Benzyloxy-2-nitrophenyl)ethanone (7g):
white solid (21.7 mg, 40%); mp 67−68 °C; IR (KBr) ν = 1528 (NO2),
1
1680 (CO) cm−1; H NMR (CDCl3, 500 MHz) δ 7.54−7.22 (m,
yellow solid (52.0 mg, 78%); mp 121−123 °C; IR (KBr) ν = 1535
(NO2) cm−1; 1H NMR (CDCl3, 500 MHz) δ 7.30 (t, J = 8.0 Hz, 1H),
7.06−7.03 (m, 2H), 4.27 (t, J = 6.0 Hz, 2H), 3.93 (s, 3H), 2.95 (t, J =
6.0 Hz, 2H); 13C NMR (CDCl3, 125 MHz) δ 157.6, 148.5, 144.2, 130.0,
120.3, 116.4, 110.9, 65.3, 62.5, 30.9; MS (EI, 70 eV) m/z = 222 (40)
[M+], 161 (100); HRMS (EI) for C10H10N2O4 calcd 222.0641, found
222.0648.
8H), 5.18 (s, 2H), 2.52 (s, 3H); 13C NMR (CDCl3, 125 MHz) δ 198.2,
160.5, 148.1, 135.2, 129.6, 129.2, 128.9, 128.7, 127.6, 119.8, 110.4, 71.0,
29.5; MS (EI, 70 eV) m/z = 271(2) [M+], 91(100); HRMS (EI) for
C15H13NO4 calcd 271.0845, found 271.0849.
1-(4-Fluoro-2-nitrophenyl)ethanone (7i):
General Procedure for the Synthesis of 2-Nitrated Aryl
Ketones. o-Nitro aryl ketone O-methyl oximes 6 (0.2 mmol), 12 N HCl
(1 mL), and CH2Cl2 (1 mL) were added to a 25 mL sealed tube.
Then the mixture was stirred at 100 °C for 24 h. Upon completion,
the reaction mixture was extracted with CH2Cl2, dried over Na2SO4, and
filtered. The solvent was then removed under reduce pressure and the
residue was purified by flash column chromatography on silica gel (100−
200 mesh) with petroleum ether/EtOAc (3:1, v/v) as the eluent.
1-(2-Nitrophenyl)ethanone (7a):49
yellow oil (26.0 mg, 71%); IR (neat) ν = 1531 (NO2), 1706 (CO)
cm−1; 1H NMR (CDCl3, 500 MHz) δ 7.77 (dd, J1 = 8.0 Hz, J2 = 2.5 Hz,
1H), 7.52−7.42 (m, 2H), 2.55 (s, 3H); 13C NMR (CDCl3, 125 MHz) δ
1
4
198.2, 162.7 (d, JF−C = 255.0 Hz), 147.3, 133.7 (d, JF−C = 3.8 Hz),
129.6 (d, 3JF−C = 8.8 Hz), 121.1 (d, 2JF−C = 21.3 Hz), 112.2 (d, 2JF−C
=
26.3 Hz), 29.9; MS (EI, 70 eV) m/z =183(1) [M+], 168(100); HRMS
(EI) for C8H6FNO3 calcd 183.0332, found 183.0337.
1-(4-Chloro-2-nitrophenyl)ethanone (7j):52
yellow oil (28.1 mg, 85%); IR (neat) ν = 1531 (NO2), 1706 (CO)
cm−1; 1H NMR (CDCl3, 500 MHz) δ 8.11 (dd, J1 = 8.5 Hz, J2 = 1.5 Hz,
1H), 7.75 (dd, J1 = 7.0 Hz, J2 = 1.0 Hz, 1H), 7.73−7.44 (m, 2H), 2.57 (s,
3H); 13C NMR (CDCl3, 125 MHz) δ 199.7, 145.8, 138.0, 134.1, 130.6,
127.3, 124.3, 30.1; MS (EI, 70 eV) m/z =165 (1) [M+], 150 (100);
HRMS (EI) for C8H7NO3 calcd 165.0426, found 165.0431.
1-(4-Methyl-2-nitrophenyl)ethanone (7b):50
white solid (30.7 mg, 77%); mp 56−57 °C (lit.52 mp 55−56 °C); IR
1
(KBr) ν = 1537 (NO2), 1707 (CO) cm−1; H NMR (CDCl3, 500
MHz) δ 8.08 (d, J = 2.0 Hz, 1H), 7.70 (dd, J1 = 8.5 Hz, J2 = 2.5 Hz, 1H),
7.43 (d, J = 8.5 Hz, 1H), 2.56 (s, 3H); 13C NMR (CDCl3, 125 MHz) δ
198.3, 146.6, 136.8, 135.9, 134.1, 128.7, 124.6, 29.9; MS (EI, 70 eV) m/z
= 199 (1) [M+], 184 (100); HRMS (EI) for C8H6ClNO3 calcd
199.0036, found 199.0044.
1-(4-Bromo-2-nitrophenyl)ethanone (7l):53
white solid (26.9 mg, 75%); mp 39−40 °C; IR (KBr) ν = 1534 (NO2),
1687 (CO) cm−1; 1H NMR (CDCl3, 500 MHz) δ 7.86 (s, 1H), 7.51
(d, J = 7.5 Hz, 1H), 7.36 (d, J = 7.5 Hz, 1H), 2.54 (s, 3H), 2.50 (s, 3H);
13C NMR (CDCl3, 125 MHz) δ 199.5, 146.3, 141.9, 134.9, 134.5, 127.5,
124.6, 30.0, 21.1; MS (EI, 70 eV) m/z = 179(2) [M+], 164(100); HRMS
(EI) for C9H9NO3 calcd 179.0582, found 179.0585.
yellow solid (38.1 mg, 78%); mp 67−68 °C (lit.53 mp 70 °C); IR (KBr)
ν = 1533 (NO2), 1706 (CO) cm−1; 1H NMR (CDCl3, 500 MHz) δ
8.23 (d, J = 2.0 Hz, 1H), 7.86 (dd, J1 = 8.0 Hz, J2 = 1.5 Hz, 1H), 7.35 (d,
J = 8.0 Hz, 1H), 2.55 (s, 3H); 13C NMR (CDCl3, 125 MHz) δ 198.4,
146.5, 137.1, 136.3, 128.8, 127.4, 124.3, 28.9; MS (EI, 70 eV) m/z = 243
(2) [M+], 228 (100); HRMS (EI) for C8H6BrNO3 calcd 242.9531,
found 242.9527.
1-(4-Methoxy-2-nitrophenyl)ethanone (7d):51
1-(4-Iodo-2-nitrophenyl)ethanone (7n):53
white solid (35.1 mg, 90%); mp 50−51 °C (lit.51 mp 49−50 °C);
1
IR (KBr) ν = 1539 (NO2), 1692 (CO) cm−1; H NMR (CDCl3,
500 MHz) δ 7.48 (d, J = 8.5 Hz, 1H), 7.43 (d, J = 2.5 Hz, 1H), 7.17 (dd,
J1 = 8.5 Hz, J2 = 2.5 Hz, 1H), 3.92 (s, 3H), 2.52 (s, 3H); 13C NMR
(CDCl3, 125 MHz) δ 198.1, 161.5, 148.3, 129.6, 128.8, 118.9, 109.4,
56.2, 29.5 ; MS (EI, 70 eV) m/z = 195(2) [M+], 180(100); HRMS (EI)
for C9H9NO4 calcd 195.0532, found 195.0527.
white solid (23.3 mg, 40%); mp 37−38 °C; IR (KBr) ν = 1523 (NO2),
1689 (CO) cm−1; 1H NMR (CDCl3, 500 MHz) δ 8.41 (d, J = 1.5 Hz,
1H), 8.06 (dd, J1 = 8.0 Hz, J2 = 1.5 Hz, 1H), 7.19 (d, J = 7.5 Hz, 1H), 2.55
(s, 3H); 13C NMR (CDCl3, 125 MHz) δ 198.6, 146.2, 143.0, 136.9,
133.1, 128.7, 95.0, 29.9; MS (EI, 70 eV) m/z = 291(2) [M+], 176(100);
HRMS (EI) for C8H6INO3 calcd 290.9392, found 290.9387.
1-(4-Nitro-2-nitrophenyl)ethanone (7p):54
1-(5-Methoxy-2-nitrophenyl)ethanone (7f):51
white solid (19.5 mg, 50%); mp 70−71 °C (lit.51 69−70 °C); IR (KBr) ν
= 1508 (NO2), 1705 (CO) cm−1; H NMR (CDCl3, 500 MHz) δ
1
white solid (17.7 mg, 42%); mp 46−47 °C (lit.54 mp 41−42 °C);
8.16 (d, J = 9.5 Hz, 1H), 7.01 (dd, J1 = 9.0 Hz, J2 = 1.0 Hz, 1H), 6.79 (d,
J = 8.0 Hz, 1H), 3.93 (s, 3H), 2.54 (s, 3H); 13C NMR (CDCl3,
1
IR (KBr) ν = 1535 (NO2), 1717 (CO) cm−1; H NMR (CDCl3,
M
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500 MHz) δ 8.97 (d, J = 2.0 Hz, 1H), 8.59 (dd, J1 = 8.5 Hz, J2 = 2.0 Hz,
1H), 7.66 (d, J = 8.5 Hz, 1H), 2.63 (s, 3H); 13C NMR (CDCl3,
125 MHz) δ 197.6, 148.4, 146.0, 142.9, 128.8, 128.7, 120.1, 30.1; MS
(EI, 70 eV) m/z = 210(2) [M+], 195(100); HRMS (EI) for C8H6N2O5
calcd 210.0277, found 210.0284.
procedure.28 The procedure for using 10 as a catalyst for the nitration of
5a: 5a (44.8 mg, 0.3 mmol), 10 (17.7 mg, 0.03 mmol), AgNO2 (92.3 mg,
0.6 mmol), K2S2O8 (162.0 mg, 0.6 mmol), phenanthrene (21.4 mg,
0.12 mmol, internal standard), and anhydrous DCE (3.5 mL) were
sequentially added to a 25-mL Schlenk flask equipped with a high-
vacuum PTFE valve-to-glass seal. Then the flask was sealed and stirred at
110 °C for 48 h. Upon completion, the resulting mixture was diluted
with CH2Cl2 (10 mL) and filtered through Celite. A sample was taken
for GC analysis, and 75% yield of 6a was determined.
1-(4-Methylsulfonyl-2-nitrophenyl)ethanone (7r):
Preparation of 2-Phenyl-d5-quinoxaline (1a-d5).
white solid (42.8 mg, 88%); mp 149−150 °C; IR (KBr) ν = 1536 (NO2),
1708 (CO) cm−1; 1H NMR (CDCl3, 500 MHz) δ 8.70 (d, J = 1.5 Hz,
1H), 8.31 (dd, J1 = 8.0 Hz, J2 = 1.5 Hz, 1H), 7.66 (d, J = 7.5 Hz, 1H), 3.16
(s, 3H), 2.62 (s, 3H); 13C NMR (CDCl3, 125 MHz) δ 198.1, 145.9,
143.3, 142.5, 133.0, 128.8, 124.0, 44.3, 30.1; MS (EI, 70 eV) m/z =
243(2) [M+], 228(100); HRMS (EI) for C9H9NO5S calcd 243.0201,
found 243.0204.
1-(2-Nitrophenyl)propanone (7s):
yellow oil (35.1 mg, 98%); IR (neat) ν = 1529 (NO2), 1706 (CO)
cm−1; 1H NMR (CDCl3, 500 MHz) δ 8.14 (dd, J1 = 8.0 Hz, J2 = 1.0 Hz,
1H), 7.75−7.72 (m, 1H), 7.63−7.59 (m, 1H), 7.39 (dd, J1 = 8.0 Hz, J2 =
1.5 Hz, 1H), 2.81 (q, J = 7.5 Hz, 2H), 1.28 (t, J = 7.5 Hz, 3H); 13C NMR
(CDCl3, 125 MHz) δ 203.2, 145.7, 138.3, 134.2, 130.3, 127.2, 124.4,
36.4, 8.2; MS (EI, 70 eV) m/z = 179(2) [M+], 150(100); HRMS (EI)
for C9H9NO3 calcd 179.0582, found 179.0584.
Compound 12 was synthesized via a modified procedure according to
a previous report.56 Benzene-d6 (0.6 mL, 6.4 mmol), AlCl3 (1.07 g,
8.0 mmol), and anhydrous CS2 (1.5 mL) were added to a 10-mL flask
under argon atmosphere. To the mixture was dropwise added a solution
of acetyl chloride (0.628 g, 8.05 mmol) in anhydrous CS2 (2.5 mL) at
5 °C. The resulting mixture was allowed to warm to room temperature
and stirred for 5 h. Then the mixture was heated to reflux for 3 h. After
being cooled to room temperature, the resulting mixture was poured
out to ice water and extracted with CH2Cl2 (3 × 30 mL). The orgnic
layer was washed with saturated aqueous Na2CO3 (20 mL) and brine
(20 mL) and then dried over Na2SO4. After evaporation of the solvent
under vacuum, the residue was purified by column chromatography on
silica gel (100−200 mesh) using petroleum ether−EtOAc (15:1) as
eluent to give 12 (0.68 g, 85%) as a colorless oil: MS (EI, 70 eV) m/z =
125 (27) [M+].
8-Nitro-3,4-dihydro-1(2H)naphthalenone (7v):55
yellow solid (36.3 mg, 95%); mp 150−151 °C (lit.55 mp 147−150 °C);
1
IR (KBr) ν = 1540 (NO2), 1688 (CO) cm−1; H NMR (CDCl3,
500 MHz) δ 7.56 (t, J = 8.0 Hz, 1H), 7.45 (d, J = 8.0 Hz, 1H), 7.32 (d, J =
7.5 Hz, 1H), 3.04 (t, J = 6.0 Hz, 2H), 2.73 (t, J = 6.5 Hz, 2H), 2.22−2.17
(m, 2H); 13C NMR (CDCl3, 125 MHz) δ 194.4, 149.9, 146.5, 133.2,
131.4, 124.7, 121.3, 39.0, 29.7, 22.6; MS (EI, 70 eV) m/z = 191(24)
[M+], 147 (31); HRMS (EI) for C10H9NO3 calcd 191.0582, found
191.0587.
Compound 13 was synthesized according to the literature procedure.57
The obtained 12 (0.375 g, 3.0 mmol), CH2Cl2 (15 mL), CH3OH (6 mL),
and TBA·Br357 were added to a 50-mL flask. The mixture was stirred at
30 °C for 2 h until it turned light yellow. Then the solvent was removed
under vacuum, and the residue was diuted with water (10 mL) and
extracted with ether (3 × 20 mL). The orgnic layer was then dried over
Na2SO4, filtered, and evaporated. The crude product was purified by
column chromatography on silica gel (100−200 mesh) using petroleum
ether-EtOAc (10:1) as eluent to give 13 (0.47 g, 77%): MS (EI, 70 eV)
m/z = 203 (2) [M+], 205 (2) [M++2].
5-Nitro-2,3-dihydro-4H-1-benzopyran-4-one (7w):
white solid (30.1 mg, 78%); mp 149−150 °C; IR (KBr) ν = 1539 (NO2),
1
1693 (CO) cm−1; H NMR (CDCl3, 500 MHz) δ 7.55 (dd, J1 =
8.5 Hz, J2 = 3.0 Hz, 1H), 7.18 (dd, J1 = 8.5 Hz, J2 = 1.0 Hz, 1H), 7.06 (dd,
J1 = 8.0 Hz, J2 = 1.0 Hz, 1H), 4.63 (t, J = 6.5 Hz, 2H), 2.89 (t, J = 6.5 Hz,
2H); 13C NMR (CDCl3, 125 MHz) δ 187.5, 162.2, 149.3, 135.3, 121.2,
115.7, 113.0, 67.2, 37.6; MS (EI, 70 eV) m/z = 193(50) [M+], 165(100);
HRMS (EI) for C9H7NO4 calcd 193.0375, found 193.0379.
Mechanistic Studies. Nitration of 2-phenylpyridine (3a) Cata-
lyzed by Complex 8. Complex 8 was prepared according to the
literature procedure.27 The analytical data were in accordance with the
reported ones.27
Compound 1a-d5 was synthesized according to the literature pro-
58
cedure.37 To a suspension of 13 (0.41 g, 2.0 mmol) and HClO4·SiO2
(0.2 g) in CH3CN (10 mL) was dropwise added a solution of
o-phenyldiamine 14 (0.26 g, 2.4 mmol) in CH3CN (2 mL), and the
mixture was stirred at room temperature for 5 h. After completion
(monitored by TLC), the reaction mixture was filtered and washed with
CH2Cl2 (20 mL). The filtrate was concentrated, and the residue was
purified by column chromatography on silica gel (100−200 mesh) using
petroleum ether−EtOAc (6:1, V/V) as eluent to obtain pure 2-phenyl-
d5-quinoxaline (1a-d5) as a yellow solid (0.37 g, 87%): mp 151−152 °C;
1H NMR (CDCl3, 500 MHz) δ 9.33 (s, 1H), 8.16 (dd, J1 = 8.0 Hz, J2 =
1.0 Hz, 1H), 8.12 (dd, J1 = 8.0 Hz, J2 = 1.0 Hz, 1H), 7.80−7.73 (m, 2H);
13C NMR (CDCl3, 125 MHz) δ 151.8, 143.3, 142.3, 141.6, 136.6, 130.2,
130.0−129.7 (m, 1C), 129.6, 129.5, 129.1, 128.9−128.4 (m, 2C),
127.4−126.9 (m, 2C); MS (EI, 70 eV) m/z = 211 (100) [M+], 184 (33);
HRMS (EI) for C14H5D5N2 calcd 211.1158, found 211.1165.
The procedure for using 8 as a catalyst for nitration of 3a: 3a (46.6 mg,
0.3 mmol), 8 (9.6 mg, 0.015 mmol), AgNO2 (92.3 mg, 0.6 mmol),
K2S2O8 (162.0 mg, 0.6 mmol), phenanthrene (21.4 mg, 0.12 mmol,
internal standard), and anhydrous DCE (3.5 mL) were sequentially
added to a 25-mL Schlenk flask equipped with a high-vacuum PTFE
valve-to-glass seal. Then the flask was sealed and stirred at 130 °C for
48 h. Upon completion, the resulting mixture was diluted with CH2Cl2
(10 mL) and filtered through Celite. Sample was taken for GC analysis,
and 67% yield of 4a was determined.
Nitration of Acetophenone O-Methyl Oxime 5a Catalyzed by
Complex 10. Complex 10 was prepared according to the literature
N
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Preparation of 2-(2-Iodophenyl-d4)quinoxaline (15).
Celite. After evaporation of the solvent under vacuum, the residue was
purified by column chromatography on silica gel (100−200 mesh) using
petroleum ether−EtOAc (4:1, V/V) as eluent. A mixture of 2a-d4 and 2a
was determined on the basis of 1H NMR spectral analysis. Based on the
integrations related to different hydrogen resonances, the kinetic isotope
effect is calculated to be kH/kD = 4.6 0.2.
Determination of Intermolecular Kinetic Isotope Effect between
5a and 5a-d5. Compound 5a-d5 was prepared according to the
reported procedure.61 Procedure for determination of intermolecular
isotope effect: To a 25-mL Schlenk flask equipped with a high-vacuum
PTFE valve-to-glass seal were sequentially added acetophenone
O-methyl oxime 5a (22.4 mg, 0.15 mmol), 5a-d5 (23.1 mg, 0.15 mmol),
Pd(OCOCF3)2 (10.0 mg, 0.03 mmol), AgNO2 (92.4 mg, 0.6 mmol),
K2S2O8 (162.0 mg, 0.6 mmol), and anhydrous DCE (3.5 mL). The flask
was sealed and heated to 110 °C for 24 h. The resulting mixture was
diluted with CH2Cl2 (10 mL) and filtered through Celite. After
evaporation of the solvent under vacuum, the residue was purified by
column chromatography on silica gel (100−200 mesh) using petroleum
ether−EtOAc (4:1, V/V) as eluent. A mixture of 6a-d4 and 6a was
Compound 15 was synthesized via a modified procedure according to
previous report.59 To a 25-mL flask were added 2-phenyl-d5-quinoxaline
(1a-d5) (211.0 mg, 1.0 mmol), Pd(OAc)2 (22.4 mg, 0.1 mmol), Bu4NI
(738.0 mg, 2.0 mmol), PhI(OAc)2 (644.0 mg, 2.0 mmol), and AcOH
(6.0 mL). The mixture was stirred and heated to reflux for 8 h
(monitored by TLC). Upon completion, it was treated with saturated
aqueous Na2CO3 (10 mL) and CH2Cl2 (20 mL). The organic layer was
separated, and the aqueous phase was extracted with CH2Cl2 (3 × 20
mL). The combined orgnic layer was then dried over Na2SO4, filtered,
and evaporated. The residue was purified by column chromatography on
silica gel (100−200 mesh) using petroleum ether−EtOAc (4:1, v/v) as
eluent to give pure 15 (238.0 mg, 71%) as pale yellow solid: Rf =
1
determined on the basis of H NMR spectral analyses. Based on the
1
0.56 (cyclohexane-EtOAc, 3:1); mp 153−154 °C; H NMR (CDCl3,
integrations related to different hydrogen resonances, the kinetic isotope
effect is calculated to be kH/kD = 2.3 0.2.
500 MHz) δ 9.14 (s, 1H), 8.19−8.17 (m, 2H), 7.85−7.81 (m, 2H); 13C
NMR (CDCl3, 125 MHz) δ 155.7, 146.0, 142.1, 141.8, 141.5, 139.9−
139.3 (m, 1C), 130.8−130.5 (m, 2C), 130.4, 130.2, 129.6, 129.3, 128.5−
128.0 (m, 1C), 96.3; MS (EI, 70 eV) m/z = 336 (100) [M+], 209 (81);
HRMS (EI) for C14H5D4IN2 calcd 336.0062, found 336.0056.
Preparation of 2-Phenyl-1,2,3,4-d4-quinoxaline (1a-d4).
Effect of Radical Scavenger TEMPO on the Reaction. Compound
1a (61.9 mg, 0.3 mmol), Pd(OAc)2 (6.7 mg, 0.03 mmol), AgNO2
(92.3 mg, 0.6 mmol), K2S2O8 (162.0 mg, 0.6 mmol), TEMPO (0.15 or
0.6 mmol), phenanthrene (21.4 mg, 0.12 mmol, internal standard), and
anhydrous DCE (3.5 mL) were sequentially added to a 25-mL Schlenk
flask equipped with a high-vacuum PTFE valve-to-glass seal. Then the
flask was sealed and stirred at 130 °C for 48 h. Upon completion, the
resulting mixture was analyzed by GC (14% of 2a, TEMPO = 0.5 equiv;
0% of 2a, TEMPO = 2 equiv).
ASSOCIATED CONTENT
■
Compound 1a-d4 was synthesized according to the literature pro-
cedure.60 A solution of 2-(2-iodophenyl-d4)-quinoxaline (15) (0.22 g,
0.65 mmol), zinc powder (0.169 g, 2.6 mmol) in saturated aqueous
NH4Cl (3.0 mL), and THF (1.5 mL) was stirred at 25 °C overnight.
After completion (monitored by TLC), THF was removed in vacuo, and
the residue was extracted with CH2Cl2 (3 × 20 mL). The combined
organic fractions were concentrated in vacuo. The residue was purified
by column chromatography on silica gel (100−200 mesh) using
petroleum ether−EtOAc (4:1, v/v) as eluent to give desired product
1a-d4 (111.9 mg, 82%) as a yellow solid: Rf = 0.51 (cyclohexane-EtOAc,
S
* Supporting Information
X-ray structural data (CIF) of compound 2c, charts for
mechanistic studies, as well as copies of H NMR and 13C
1
NMR spectra of the products. This material is available free of
charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: ykuiliu@zjut.edu.cn
Notes
■
1
3:1); mp 148−149 °C; H NMR (CDCl3, 500 MHz) δ 9.34 (s, 1H),
8.21 (s, 1H), 8.17 (dd, J1 = 8.0 Hz, J2 = 1.5 Hz, 1H), 8.13 (dd, J1 = 8.0 Hz,
J2 = 1.5 Hz, 1H), 7.81−7.74 (m, 2H); 13C NMR (CDCl3, 125 MHz) δ
151.8, 143.3, 142.3, 141.6, 136.7, 130.2, 130.0−129.7 (m, 1C), 129.6,
129.5, 129.1, 129.0−128.4 (m, 2C), 127.4, 127.5−126.9 (m, 1C); MS
(EI, 70 eV) m/z = 210 (100) [M+], 183 (39); HRMS (EI) for
C14H6D4N2 calcd 210.1095, found 210.1096.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support from the Natural Science Foundation of China
(No. 21172197) and Zhejiang Province (No. Y4100201), the
Foundation of Science and Technology Department of Zhejiang
Province (2011R09002-09), and the opening Foundation of
Zhejiang Provincial Top Key Discipline is gratefully acknowledged.
Determination of Intramolecular Kinetic Isotope Effect of 1a-d4.
To a 25-mL Schlenk flask equipped with a high-vacuum PTFE valve-to-
glass seal were sequentially added 2-phenyl-1,2,3,4-d4-quinoxaline 1a-d4
(63.0 mg, 0.3 mmol), Pd(OAc)2 (6.7 mg, 0.03 mmol), AgNO2 (92.4 mg,
0.6 mmol), K2S2O8 (162.0 mg, 0.6 mmol), and anhydrous DCE
(3.5 mL). Then the flask was sealed and heated to 130 °C for 48 h. The
resulting mixture was diluted with CH2Cl2 (10 mL) and filtered through
Celite. After evaporation of the solvent under vacuum, the residue was
purified by column chromatography on silica gel (100−200 mesh) using
petroleum ether−EtOAc (4:1, V/V) as eluent to give the mixture of
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