Single-Step Approach toward Nitrones via Pyridinium Ylides: The DMAP-Catalyzed Reaction of Benzyl Halides with Nitrosoarenes

Article abstract of DOI:10.1021/acs.joc.1c00158

A single-step approach is reported for the preparation of nitrones from benzyl halides and nitrosoarenes via pyridinium ylides, utilizing 4-dimethylaminopyridine (DMAP) catalyst and mild reaction conditions (Li2CO3, dimethylacetamide, and room temperature). The reaction provides both keto-and aldonitrones in high yields with a wide scope for benzyl halides and nitrosoarenes. In the same reaction system, 2-methyl-2-nitrosopropane, which does not have an aryl group, also affords the corresponding N-tert-butyl nitrones from primary benzyl bromides that have an electron-withdrawing group. As an application of the reaction, methyl 2-bromo-2-phenylacetate was used to prepare the corresponding isoxazolidine by a sequential one-pot synthesis.

Full text of DOI:10.1021/acs.joc.1c00158

pubs.acs.org/joc
Article
Single-Step Approach toward Nitrones via Pyridinium Ylides: The
DMAP-Catalyzed Reaction of Benzyl Halides with Nitrosoarenes
Yeonghun Jung, Jee Eun Hong, Jae-Hwan Kwak, and Yohan Park*
Cite This: J. Org. Chem. 2021, 86, 6343−6350
Read Online
sı
*
Metrics & More
Article Recommendations
Supporting Information
ACCESS
ABSTRACT: A single-step approach is reported for the
preparation of nitrones from benzyl halides and nitrosoarenes via
pyridinium ylides, utilizing 4-dimethylaminopyridine (DMAP)
catalyst and mild reaction conditions (Li2CO3, dimethylacetamide,
and room temperature). The reaction provides both keto- and
aldonitrones in high yields with a wide scope for benzyl halides and
nitrosoarenes. In the same reaction system, 2-methyl-2-nitrosopropane, which does not have an aryl group, also affords the
corresponding N-tert-butyl nitrones from primary benzyl bromides that have an electron-withdrawing group. As an application of the
reaction, methyl 2-bromo-2-phenylacetate was used to prepare the corresponding isoxazolidine by a sequential one-pot synthesis.
with arylboronic acids,7b,c and metal-free N-arylation of oximes
INTRODUCTION
Nitrones have been actively studied and are potent neuro-
■
with diaryliodonium salts.7d,e
Recently, we reported metal-free aerobic oxidation of aryl α-
halo esters to aryl α-keto esters using 4-dimethylaminopyridine
protective agents due to the radical scavenging effect of their
1,3-dipole structure.1 The well-known neuroprotective nitro-
(DMAP) catalyst with Li2CO3 in dimethylacetamide (DMA).8
By applying this catalytic system, we expected to effectively
synthesize nitrones from nitroso compounds with benzyl
halides, abundant chemical species that are readily available.
Diverse strategies to provide nitrones starting from nitroso
compounds have been reported. They include (i) a P(NMe2)3-
mediated reaction with 1,2-dicarbonyls,9a (ii) a gold-catalyzed
reaction with electron-deficient alkynes,9b (iii) a solvent-free
silica gel-promoted reaction with diazooxindoles,9c (iv) a
proline-based organocatalytic reaction with α,β-unsaturated
aldehydes at the γ-position,9d (v) a proline-mediated reaction
with benzaldehydes,9e (vi) a reaction with sulfones,9f (vii) a
coupling reaction with N-nosylhydrazones,9g and (viii) a 2-tert-
butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2-diaza-
phosphorine (BEMP)-catalyzed reaction with aryl acetic acid
esters.9h Nevertheless, there was no reaction method for
preparing nitrones directly from nitrosoarenes using benzyl
halides. Of the eight examples given above, only reactions (vi)
and (vii) reported protocols applicable to the synthesis of both
keto- and aldonitrones.
nes α-phenyl-N-tert-butylnitrone (PBN)1a and NXY-0591b are
shown in Figure 1. PBN has been used as a positive control to
Figure 1. Neuroprotective nitrones.
evaluate the effects of reactive oxygen species (ROS)
scavenging in multiple medicinal chemistry papers.1c−f NXY-
059, which is derived from the structure of PBN, is the first
nitrone to reach clinical trials for the treatment of acute
ischemic stroke.
Nitrones are essential intermediates in the preparation of
biologically active heterocycles such as isoxazolidines, isoxazo-
lines, imidazolidin-4-ones, and β-lactams via various chemical
transformations.2 Nitrones are particularly useful compared to
other 1,3-diopoles or corresponding imines primarily because
they are relatively stable and easy to handle despite their
prompt reactivity. Owing to the biological and chemical
significance of nitrones, there are many reports of oxidative or
reductive approaches used to synthesize nitrones by starting
from hydroxylamines,3 secondary amines,4 imines,5 and nitro
compounds.6 Moreover, alternative methods to prepare
nitrones have been developed,2,7 such as condensation of N-
arylhydroxylamines with ketones,7a cross-coupling of oximes
A classic way to synthesize nitrones from nitroso compounds
̈
that was not mentioned above is Krohnke oxidation, which
involves the following three steps: conversion of primary or
Received: January 21, 2021
Published: April 23, 2021
https://doi.org/10.1021/acs.joc.1c00158
© 2021 American Chemical Society
J. Org. Chem. 2021, 86, 6343−6350
6343

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
a
secondary halides into pyridinium salts, synthesis of nitrones
from pyridinium salts with nitrosoarenes, and hydrolysis of
nitrones to aldehydes or ketones (Scheme 1a).10 To prepare
Table 1. Optimization of Reaction Conditions
̈
Scheme 1. Comparison between Krohnke Oxidation and the
Reaction Reported in This Work
b
entry
2A (equiv)
pyridine cat.
Li2CO3 (equiv)
yield (%)
1
2
3
4
5
6
7
5.0
5.0
2.0
1.2
2.0
2.0
2.0
DMAP
pyridine
DMAP
DMAP
DMAP
2.0
2.0
2.0
2.0
1.0
2.0
93 (93/7)
21 (81/19)
98 (94/6)
89 (89/11)
88 (90/10)
0
DMAP
0
a
Reaction conditions: To a 0.2 M solution of 1ab (0.2 mmol, 1.0
equiv) in DMA (1.0 mL) were added 2A, the catalyst (0.02 mmol, 10
mol %), and Li2CO3 at room temperature, and the mixture was stirred
b
for 24 h. Yields were determined by 1H NMR using 1,3,5-
trimethoxybenzene as an internal standard. In parentheses are E/Z
ratios.
̈
nitrones, Krohnke oxidation can of course be applied, but this
multistep sequential reaction theoretically requires at least 1.0
̈
equiv of pyridine. Krohnke did not mention a detailed general
protocol for preparing pyridinium salts from the corresponding
halides, as his method was focused on starting with pyridinium
sobenzene (2A) dissolved in the same DMA solvent rather
than with the O2 in air. It was confirmed that nitrone 3aA was
not observed in the absence of a pyridine catalyst or base
(entries 6 and 7).
Using the optimal reaction conditions, the reaction scope of
halides (X) in the substrates was evaluated (Table 2). In the
̈
salts. However, in recently reported examples of Krohnke
oxidation, benzyl bromides were reacted with 4.0 equiv of 4-
methylpyridine in dimethyl sulfoxide (DMSO) at room
temperature11a and benzyl iodides were reacted with excess
pyridine as a solvent at 100 °C.11b Therefore, we thought that
our previously reported catalytic pyridinium ylide system could
a b
,
Table 2. Scope of Halide Compatibility
̈
simplify the process of Krohnke oxidation and reduce the
waste of resources. Herein, we report the DMAP-catalyzed
direct synthesis of keto- and aldonitrones from corresponding
benzyl halides and nitrosoarenes (Scheme 1b). The reactions
were carried out under mild reaction conditions (Li2CO3,
DMA, and room temperature).
a
b
c
RESULTS AND DISCUSSION
Reaction conditions: see entry 3 in Table 1. Isolated yield. K2CO3
■
(2.0 equiv) was used.
To optimize the reaction conditions, we performed the
synthesis of nitrone 3aA from secondary benzyl bromide 1ab
and nitrosobenzene 2A under our previously optimized
conditions8 (Table 1). The DMAP catalyst with an excess of
2A (5.0 equiv) successfully gave 3aA (entry 1: yield, 93%; E/Z
ratio, 93/7), but pyridine did not function well as a catalyst
under the same conditions (entry 2: yield, 21%; E/Z ratio, 81/
19). According to the literature10,12 and our previously
reported work,8 pyridine catalysts form pyridinium salts with
1ab by a substitution reaction and the salts generate
pyridinium ylides under mildly basic conditions. The results
of entries 1 and 2 indicate that the higher nucleophilicity of
DMAP in comparison to pyridine is a key factor in the
successful synthesis of nitrone 3aA. The highest yield and E/Z
selectivity (entry 3: yield, 98%; E/Z ratio, 94/6) were obtained
when less 2A (2.0 equiv) was used, rather than in entry 1 (5.0
equiv). However, further reducing the concentration of 2A
(1.2 equiv) or Li2CO3 (1.0 equiv) was not effective (entry 4:
yield, 89%; E/Z ratio, 89/11; entry 5: yield, 88%; E/Z ratio,
90/10). In entries 1−5, only trace amounts of ethyl 2-oxo-2-
phenylacetate, the aerobic oxidation product of 1ab,8 were
observed by 1H nuclear magnetic resonance (NMR). In
addition, when the reactions were carried out under Ar, the
yields of 3aA were not significantly improved. This is probably
because substrate 1ab reacts predominantly with the nitro-
synthesis of nitrone 3aA from phenyl α-halo esters 1aa−c,
chloride (1aa: yield, 90%; E/Z ratio, 93/7) and bromide (1ab:
yield, 95%; E/Z ratio, 94/6) were effective leaving groups, but
iodide was not (1ac: yield, 68%; E/Z ratio, 93/7). The
reaction scope of aryls (Ar) and other functional groups (R)
was also examined using various benzyl bromides 1b−n (Table
3). As a result of changing the Ar groups, sterically hindered 1-
naphthyl 1b showed a very low yield (3bA, 19%), while less
hindered 2-naphthyl 1c gave a relatively good yield (3cA,
81%). 4-OMe, an electron-donating group (EDG), resulted in
a reduced yield (3dA, 62%), but the electron-withdrawing
groups (EWGs) 4-Br and 4-CO2Et smoothly provided the
corresponding nitrones (3eA, 87%; 3fA, 99%). Nitrones 3a−
fA, prepared from ethyl α-bromoarylacetates, exhibited E/Z
ratios ranging from 89/11 to 95/5.
As a result of changing the R groups (Table 3), methyl ester
1g and cyclic amide 1h successfully afforded the corresponding
ketonitrones (3gA, yield: 94%, E/Z ratio: 89/11; 3hA, yield:
98%, E/Z ratio: 95/5), but ketone 1i did not (3iA, yield: 44%,
E/Z ratio: 97/3), despite modification of the optimized
reaction conditions. Reports of the unsatisfactory result with
3iA can also be found in prior literature.9a Isolated yields of
3gA from nitrosobenzene (2A) with methyl 2-oxo-2-phenyl-
6344
https://doi.org/10.1021/acs.joc.1c00158
J. Org. Chem. 2021, 86, 6343−6350

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
a b
,
yields (3lA, 57%; 3mA, 85%). Primary benzyl bromides 1k−m
provided the corresponding aldonitrones 3l−nA with a very
high Z/E ratio (>99/1). Considering the reported procedures
to prepare aldonitrones using sulfones9f and N-nosylhydrazo-
nes,9g it is a limitation that only primary benzyl bromides
containing EWGs showed moderate yields.
Table 3. Scope of Aryls and Other Functional Groups
3-Bromoindolin-2-one (1h) was chosen as a substrate for
further investigation of the substituent scope of nitrosoarenes 2
because 1h can generate a very important nitrone containing
an oxindole structure (Table 4).7a,c,e Nitrosobenzenes with all
a b
,
Table 4. Scope of Nitrosoarene Compatibility
a
b
c
Reaction conditions: see entry 3 in Table 1. Isolated yield. DMAP
d
e
(20 mol %) was used. Na2CO3 (2.0 equiv) was used. Cs2CO3 (1.0
equiv) was used.
acetate and methyl 2-phenylacetate were reported, respectively,
as 85% (E isomer)9a and 87% (E/Z ratio: 95/5).9h Our
protocol gave 3gA in a higher yield (94%) but considering the
E/Z ratio (89/11), the mole fractions of the E isomer in the
three results were similar. In addition, our method showed a
similar result (yield: 98%, E/Z ratio: 95/5) compared to the
known method (yield: 95%, E isomer) of preparing 3hA by
copper-catalyzed coupling between isatin oxime and PhB-
(OH)2.7c Interestingly, 9-bromofluorene (1j) without a
carbonyl resulted in a higher yield than we expected (3jA,
73%). In other studies, isolated yields of 3jA from the
corresponding sulfone and N-nosylhydrazone were 92%9f and
84%,9g respectively. Compared to these results, 3jA was
afforded in a lower yield (73%) here. However, our method
has the advantage that 3jA was prepared directly from
commercially available 9-bromo-9H-fluorene (3j) without
further chemical transformations. The very high yield of
oxindole 3hA (98%) and the unexpectedly high yield of
fluorene 3jA (73%) were attributed to the use of cyclic
substrates to minimize steric hindrance.
a
b
Reaction conditions: see entry 3 in Table 1. Isolated yield.
of the 4-substituents tested smoothly produced the corre-
sponding nitrones 3hB−F, but substrates with EDGs tended to
result in slightly lower yields (3hB, 89%; 3hC, 89%) than
substrates with EWGs (3hD, 99%; 3hE, 99%; 3hF, 99%).
Nitrosobenzenes 2G−I, which have 3-substituents, gave the
corresponding nitrones 3hG−I in good yields (3hG, 80%;
3hH, 80%; 3hI, 82%). However, the presence of a 2-Br
substituent, which can cause steric hindrance, led to a
significantly reduced yield (3hJ, 64%). Nitrones 3hB−J,
prepared from 1h, showed E/Z ratios ranging from 89/11 to
>99/1.
In addition, primary benzyl bromides 1l−o were reacted
with 2-methyl-2-nitrosopropane (2K) to synthesize N-tert-
butyl aldonitrones that are frequently observed in neuro-
protective agents (Table 5). In the same reaction system using
DMAP as a catalyst, the corresponding N-tert-butyl aldoni-
trones 3l−oK were successfully produced in moderate yields
(52−71%) and very high Z/E ratios (>99/1). Unfortunately,
2K did not provide ketonitrones due to high steric hindrance.
As we have reported, pyridinium salt 4a was isolated (82%)
from the reaction of 1ab (1.1 equiv) with DMAP (1.0 equiv)
As expected, benzyl bromide (1k), a primary halide without
an EWG, showed a very low yield (3kA, 25%) due to the
relatively high pKa value of the pyridinium salt produced
through a substitution reaction between 1k and DMAP. Thus,
4-NO2-benzyl bromides 1l and 1m were examined as
substrates in the presence of Cs2CO3 base (1.0 equiv) and
the corresponding aldonitrones were obtained in increased
6345
https://doi.org/10.1021/acs.joc.1c00158
J. Org. Chem. 2021, 86, 6343−6350

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
8
̈
Based on the above results (eqs 1 and 2) and Krohnke’s
Table 5. Scope of 2-Methyl-2-nitrosopropane (2K)
Compatibility
report,10 a plausible mechanism was proposed (Scheme 2).
a ba
,
Scheme 2. Proposed Mechanism
a
Reaction conditions: To a 0.2 M solution of 1l−o (0.2 mmol, 1.0
equiv) in DMA (1.0 mL) were added 2K (0.4 mmol, 2.0 equiv), the
catalyst (0.02 mmol, 10 mol %), and Cs2CO3 (1.0 mmol, 1.0 equiv) at
b
room temperature, and the mixture was stirred for 24 h. Isolated
yield.
in DMA (eq 1).8 It was reacted under Ar to prevent the
formation of ethyl 2-oxo-2-phenylacetate, an aerobic oxidation
product of 1ab. In the presence of 2A (2.0 equiv) and Li2CO3
(2.0 equiv), nitrone 3aA was synthesized from 4a and isolated
in 99% yield (eq 2). The same reaction strategy was employed
for a gram-scale synthesis of nitrone 3aA (eq 3). Although the
yield declined to 81%, the potential for industrial mass
production remains. Despite the absence of aryl groups, it was
confirmed that diethyl bromomalonate (1r) also afforded the
corresponding ketonitrone 3rA in 58% yield (eq 4). As an
application of the developed method, a one-pot reaction of a
heterocycle was performed under mild reaction conditions.
Sequential addition of nitrosobenzene (2A) and ethyl acrylate
to benzyl bromide 1g afforded 3,5-substituted isoxazolidine 5
in 62% yield as a 1.5:1 mixture of diastereomers (eq 5).
The DMAP catalyst substitutes a halide of substrate 1 to form
pyridinium salt 4. A carbonate abstracts the benzylic hydrogen
of 4 to generate a pyridinium ylide 6. Then, ylide 6 reacts with
nitrosoarene 2 to provide nitrone 3 through intermediate 7.
The regenerated DMAP then undergoes the catalytic cycle
again. Upon removal of DMAP from 7, the major isomer
seems to prefer a trans-relationship between Ar1 and Ar2 to
minimize the electronic repulsion between O atoms (R
carbonyls) or the steric hindrance between aryls (RH). On
the basis of the abovementioned experimental results,
successful catalysis may require the following essential features:
(i) the electrophilicity of halide 1 must be suitable for the
reaction with DMAP; (ii) the pKa value of pyridinium salt 4
must enable generation of ylide 6; and (iii) the Ar1, Ar2, and R
must be small enough to avoid steric hindrance.
CONCLUSIONS
In summary, we have developed a catalytic single-step
approach toward nitrone construction that shortens Krohnke’s
■
̈
multistep procedure by exploiting DMAP. In the reaction of
diverse benzyl halides, the strong nucleophilicity of DMAP
enables the production of the corresponding ylides that react
with electrophilic nitroso species. When nitrones are produced,
DMAP is regenerated and then undergoes the catalytic cycle
again. A neuroprotective skeleton, N-tert-butylnitrone, was also
accessible in the developed reaction system, and a privileged
scaffold, isoxazolidine, was prepared through the correspond-
ing nitrone by a sequential one-pot reaction. Our new
organocatalytic system with mild reaction conditions provides
a simple and effective method to synthesize nitrones directly
from benzyl halides and nitrosoarenes.
EXPERIMENTAL SECTION
■
General. All reagents and solvents from commercial sources were
used without further purification. Reactions were monitored by thin-
layer chromatography (TLC) using precoated silica gel 60 F254 plates
(Merck) and a UV light detector (254 nm). Flash column
chromatography was performed over silica gel (70−230 mesh)
purchased from Merck. Melting points (mp) were measured in open
capillary tubes by means of a Buchi B-540 instrument without
̈
1
correction. H NMR and 13C{1H} NMR spectra were recorded on a
6346
https://doi.org/10.1021/acs.joc.1c00158
J. Org. Chem. 2021, 86, 6343−6350

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
Varian VNMRS500 (500 MHz) spectrometer. Chemical shifts are
reported in parts per million (ppm, δ) and referenced to residual
solvent or tetramethylsilane (TMS). Gas chromatography−high-
resolution mass spectrometry (GC−HRMS) was performed on JEOL
JMS-AX 505wA and JEOL JMS-HX/HX 110A magnetic sector high-
resolution mass spectrometers.
Preparation of Benzyl Halides 1. All substrates 1 except ethyl 2-
bromo-2-(naphthalen-1-yl)acetate (1b), ethyl 2-bromo-2-(naphtha-
len-2-yl)acetate (1c), ethyl 2-bromo-2-(4-methoxyphenyl)acetate
(1d), ethyl 4-(1-bromo-2-ethoxy-2-oxoethyl)benzoate (1f), and 3-
bromoindolin-2-one (1h) were commercially available. Substrates
1b−d, 1f, and 1h were prepared by literature procedures.8,13
Preparation of Nitroso Compounds 2. Nitrosobenzene (2A),
N,N-dimethyl-4-nitrosoaniline (2B), and 2-methyl-2-nitrosopropane
(2K) were commercially available. 1-Methoxy-4-nitrosobenzene
(2C), 1-bromo-4-nitrosobenzene (2D), ethyl 4-nitrosobenzoate
(2E), 1-(4-nitrosophenyl)ethan-1-one (2F), 1-methoxy-3-nitrosoben-
zene (2G), ethyl 3-nitrosobenzoate (2H), 1-(3-nitrosophenyl)ethan-
1-one (2I), and 1-bromo-2-nitrosobenzene (2J) were prepared by
literature procedures.9a,14
Representative Procedure for Nitrones 3. To a 0.2 M solution of
benzyl bromide (1ab, 0.2 mmol, 48.5 mg, 1.0 equiv) in N,N-
dimethylacetamide (DMA, 1.0 mL) were added nitrosobenzene (2A,
0.4 mmol, 42.8 mg, 2.0 equiv), 4-dimethylaminopyridine (DMAP,
0.02 mmol, 2.4 mg, 10 mol %), and Li2CO3 (0.4 mmol, 29.6 mg, 2.0
equiv) at room temperature. After 24 h, the reaction mixture was
diluted with EtOAc (30 mL) and washed with brine (30 mL × 3).
The extract was dried over anhydrous MgSO4. After filtration of the
solid, the solvent in the filtrate was removed in vacuo, and the residue
was purified by silica gel column chromatography (10−30% EtOAc/
n-hexane) to give the corresponding nitrones 3aA.
3H) ppm; 13C{1H} NMR (125 MHz, CDCl3) δ 163.4, 148.7, 133.7,
130.8, 130.4, 129.2, 129.0, 128.0, 127.1, 126.4, 125.3, 124.7, 123.3,
62.2, 13.6 ppm; HRMS (FAB) m/z: [M + H]+ calcd for C20H18NO3
320.1287; found: 320.1285.
(E)-2-Ethoxy-1-(naphthalen-2-yl)-2-oxo-N-phenylethan-1-imine
oxide (3cA). Flash column chromatography: 10−30% EtOAc/n-
hexane; Yield: 51.7 mg, 81%; yellow solid; mp 106−108 °C; 1H NMR
(500 MHz, CDCl3) δ 9.03−9.02 (m, 1H), 8.00 (dd, J = 8.8, 1.9 Hz,
1H), 7.94−7.87 (m, 2H), 7.85−7.82 (m, 1H), 7.58−7.49 (m, 4H),
7.47−7.44 (m, 3H), 4.08 (q, J = 7.1 Hz, 2H), 0.95 (t, J = 7.1 Hz, 3H)
ppm; 13C{1H} NMR (125 MHz, CDCl3) δ 164.0, 148.5 134.2 132.8,
130.2 129.5, 129.3, 129.2, 128.0, 127.9 126.6 124.9 123.5 62.5, 13.4
ppm; HRMS (FAB) m/z: [M + H]+ calcd for C20H18NO3 320.1287;
found: 320.1283.
(E)-2-Ethoxy-1-(4-methoxyphenyl)-2-oxo-N-phenylethan-1-
imine oxide (3dA). Flash column chromatography: 10−30% EtOAc/
n-hexane; Yield: 37.1 mg, 62%; yellow solid; mp 76−79 °C; 1H NMR
(500 MHz, CDCl3) δ 8.29−8.22 (m, 2H), 7.55−7.47 (m, 2H), 7.46−
7.40 (m, 3H), 7.00−6.95 (m, 2H), 4.02 (q, J = 7.2 Hz, 2H), 3.86 (s,
3H), 0.92 (t, J = 7.1 Hz, 3H) ppm; 13C{1H} NMR (125 MHz,
CDCl3) δ 164.1, 161.4, 148.3, 140.6, 130.6, 129.9, 129.1, 123.5, 121.7,
113.8, 62.4, 55.4, 13.4 ppm; HRMS (FAB) m/z: [M + H]+ calcd for
C17H18NO4 300.1236; found: 300.1233.
(E)-1-(4-Bromophenyl)-2-ethoxy-2-oxo-N-phenylethan-1-imine
oxide (3eA). Flash column chromatography: 10−30% EtOAc/n-
1
hexane; Yield: 60.6 mg, 87%; yellow solid; mp 96−98 °C; H NMR
(500 MHz, CDCl3): δ 8.17−8.05 (m, 2H), 7.61−7.58 (m, 2H),
7.52−7.42 (m, 5H), 4.03 (q, J = 7.2 Hz, 2H), 0.92 (t, J = 7.2 Hz, 3H)
ppm; 13C{1H} NMR (125 MHz, CDCl3) δ 163.6, 148.4, 139.9, 131.7,
130.3, 130.1, 129.2, 128.0, 125.0, 123.3, 62.6, 13.4 ppm; HRMS
(FAB) m/z: [M + H]+ calcd for C16H15BrNO3 348.0235; found:
348.0231.
Gram-Scale Procedure for Nitrone 3aA. To a 0.3 M solution of
ethyl α-bromophenylacetate (1ab, 97%, Sigma-Aldrich; MW, 243.10
g/mol, 5.84 mmol, 1.46 g, 1.0 equiv) in anhydrous N,N-
dimethylacetamide (DMA, 99.8%, Sigma-Aldrich, 20 mL) were
added nitrosobenzene (2A, >97%, Sigma-Aldrich; MW, 107.11 g/
mol, 11.7 mmol, 1.25 g, 2.0 equiv), 4-dimethylaminopyridine
(DMAP, ≥99.0%, Sigma-Aldrich; MW, 122.17 g/mol, 0.58 mmol,
71.0 mg, 10 mol %), and Li2CO3 (≥99.0%, Sigma-Aldrich; MW,
73.89 g/mol, 11.7 mmol, 865 mg, 2.0 equiv) at room temperature.
After 24 h, the reaction mixture was diluted with EtOAc (0.9 L) and
washed with brine until DMA was removed. Particularly, during the
first washing process with brine, the product can migrate to the
aqueous layer with DMA. If the product is present in the aqueous
layer after checking by TLC, it must be extracted again with EtOAc.
The extract was dried over anhydrous MgSO4. After filtration of the
solid, the solvent in the filtrate was removed in vacuo, and the residue
was purified by silica gel column chromatography (10−30% EtOAc/
n-hexane) to give nitrone 3aA (yield: 1.27 g, 81%; yellow solid).
Assignment of Diastereomeric Ratios and Configurations.
Diastereomeric ratios were determined by integration of appropriate
(E)-2-Ethoxy-1-(4-(ethoxycarbonyl)phenyl)-2-oxo-N-phenyle-
than-1-imine oxide (3fA). Flash column chromatography: 10−30%
EtOAc/n-hexane; Yield: 67.6 mg, 99%; yellow solid; mp 64−65 °C;
1H NMR (500 MHz, CDCl3): δ 8.27−8.21 (m, 2H), 8.15−8.11 (m,
2H), 7.56−7.50 (m, 2H), 7.48−7.43 (m, 3H), 4.40 (q, J = 7.1 Hz,
2H), 4.05 (q, J = 7.1 Hz, 2H), 1.41 (t, J = 7.2 Hz, 3H), 0.93 (t, J = 7.1
Hz, 3H) ppm; 13C{1H} NMR (125 MHz, CDCl3) δ 165.7, 163.5,
148.4, 140.0, 133.1, 131.9, 130.4, 129.5, 129.2, 128.5, 123.3, 62.6,
61.3, 14.3, 13.4 ppm; HRMS (FAB) m/z: [M + H]+ calcd for
C19H20NO5 342.1341; found: 342.1344.
(E)-2-Methoxy-2-oxo-N,1-diphenylethan-1-imine oxide (3gA).
Flash column chromatography: 10−30% EtOAc/n-hexane; Yield:
1
48.0 mg, 94%; yellow solid; mp 86−87 °C; H NMR (500 MHz,
CDCl3): δ 8.16−8.11 (m, 2H), 7.53−7.43 (m, 8H), 3.56 (s, 3H)
ppm; 13C{1H} NMR (125 MHz, CDCl3) δ 164.5, 148.4, 140.5, 130.9,
130.2, 129.2, 128.6, 128.5, 124.4, 123.2, 53.0 ppm; HRMS (FAB) m/
z: [M + H]+ calcd for C15H14NO3 256.0974; found: 256.0978.
(E)-2-Oxo-N-phenylindolin-3-imine oxide (3hA). Flash column
chromatography: 25−100% EtOAc/n-hexane; Yield: 46.9 mg, 98%;
1
1
orange solid; mp 195−196 °C; H NMR (500 MHz, DMSO-d6) δ
signals in H NMR spectra of isolated product mixtures. When the
1
10.75 (s, 1H), 8.27 (d, J = 7.4 Hz, 1H), 7.60−7.47 (m, 5H), 7.40 (td,
J = 7.7, 1.3 Hz, 1H), 7.07 (td, J = 7.6, 1.0 Hz, 1H), 6.90 (d, J = 7.8 Hz,
1H) ppm; 13C{1H} NMR (125 MHz, DMSO-d6) δ 160.4, 146.9,
141.5, 135.0, 132.8, 130.7, 129.3, 124.7, 124.4, 122.3, 118.9, 110.3
ppm; HRMS (FAB) m/z: [M + H]+ calcd for C14H11N2O2 239.0821;
found: 239.0818.
minor isomer could not be distinguished even after enlarging the H
NMR spectrum, the isomeric ratio was recorded as >99/1. In all cases,
no attempt was made to separate isomers. Configurations of nitrones
3 were determined as E or Z according to the literature studies.7c,e,9a,h
(E)-2-Ethoxy-2-oxo-N,1-diphenylethan-1-imine oxide (3aA).
Flash column chromatography: 10−30% EtOAc/n-hexane; Yield:
1
(E)-2-Oxo-N,1,2-triphenylethan-1-imine oxide (3iA). Flash col-
umn chromatography: 10−30% EtOAc/n-hexane; Yield: 24.0 mg,
44%; yellow solid; mp 138−140 °C; 1H NMR (500 MHz, CDCl3): δ
1H NMR (500 MHz, CDCl3) δ 8.26−8.19 (m, 2H), 7.74−7.70 (m,
2H), 7.49 (ddt, J = 7.8, 7.1, 1.3 Hz, 1H), 7.46−7.43 (m, 3H), 7.37−
7.32 (m, 4H), 7.26−7.20 (m, 3H) ppm; 13C{1H} NMR (125 MHz,
CDCl3) δ 191.2, 147.5, 136.6, 134.2, 131.0, 130.4, 130.0, 129.5, 129.3,
129.0, 128.9, 128.8, 128.7, 128.5, 127.8, 124.4 ppm; HRMS (FAB)
m/z: [M + H]+ calcd for C20H16NO2 302.1181; found: 302.1185.
N-Phenyl-9H-fluoren-9-imine oxide (3jA). Flash column chroma-
tography: 10−30% EtOAc/n-hexane; Yield: 39.8 mg, 73%; yellow
solid; mp 184−185 °C; 1H NMR (500 MHz, CDCl3) δ 8.93 (ddd, J =
51.0 mg, 95%; yellow solid; mp 67−69 °C; H NMR (500 MHz,
CDCl3): δ 8.22−8.16 (m, 2H), 7.58−7.40 (m, 8H), 4.04 (q, J = 7.1
Hz, 2H), 0.94 (t, J = 7.2 Hz, 3H) ppm; 13C{1H} NMR (125 MHz,
CDCl3) δ163.9, 148.4, 140.8, 130.9, 130.1, 129.2, 128.6, 128.4, 124.4,
123.4, 62.4, 13.4 ppm; HRMS (FAB) m/z: [M + H]+ calcd for
C16H16NO3 270.1130; found: 270.1136.
(E)-2-Ethoxy-1-(naphthalen-1-yl)-2-oxo-N-phenylethan-1-imine
oxide (3bA). Flash column chromatography: 10−30% EtOAc/n-
hexane; Yield: 12.1 mg, 19%; yellow solid; mp 114−115 °C; 1H NMR
(500 MHz, CDCl3) δ 7.97 (d, J = 8.2 Hz, 1H), 7.94−7.91 (m, 1H),
7.76−7.73 (m, 1H), 7.69 (dd, J = 7.1, 1.2 Hz, 1H), 7.65−7.61 (m,
2H), 7.59−7.49 (m, 6H), 4.04 (q, J = 7.1 Hz, 2H), 0.94 (t, J = 7.1 Hz,
6347
https://doi.org/10.1021/acs.joc.1c00158
J. Org. Chem. 2021, 86, 6343−6350

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
7.6, 1.3, 0.7 Hz, 1H), 7.70−7.67 (m, 1H), 7.65−7.62 (m, 1H), 7.62−
7.58 (m, 3H), 7.55−7.51 (m, 2H), 7.49 (td, J = 7.5, 1.3 Hz, 1H), 7.42
(td, J = 7.6, 1.2 Hz, 1H), 7.23 (td, J = 7.5, 1.0 Hz, 1H), 6.89 (ddd, J =
8.0, 7.4, 1.1 Hz, 1H), 5.89 (dt, J = 8.0, 0.8 Hz, 1H) ppm; 13C{1H}
NMR (125 MHz, CDCl3) δ 147.1, 145.5, 139.3, 139.1, 132.4, 131.2,
130.8, 130.4, 130.2, 129.2, 128.9, 127.3, 127.1, 123.9, 120.2, 119.7
ppm; HRMS (FAB) m/z: [M + H]+ calcd for C19H14NO 272.1075;
found: 272.1072.
122.4, 118.6, 110.4, 61.6, 14.6 ppm; HRMS (FAB) m/z: [M + H]+
calcd for C17H15N2O4 311.1032; found: 311.1033.
(E)-N-(4-Acetylphenyl)-2-oxoindolin-3-imine oxide (3hF). Flash
column chromatography: 25−100% EtOAc/n-hexane; Yield: 55.5 mg,
99%; orange solid; mp 196−198 °C; 1H NMR (500 MHz, DMSO-d6)
δ 10.81 (s, 1H), 8.27 (d, J = 7.6 Hz, 1H), 8.08 (d, J = 8.5 Hz, 2H),
7.73 (d, J = 8.5 Hz, 2H), 7.42 (t, J = 7.1 Hz, 1H), 7.08 (t, J = 7.6 Hz,
1H), 6.91 (d, J = 7.8 Hz, 1H), 2.66 (s, 3H) ppm; 13C{1H} NMR (125
MHz, DMSO-d6) δ 197.7, 160.5, 149.7, 141.7, 138.3, 135.5, 133.1,
129.4, 125.0, 124.8, 122.4, 118.7, 110.4, 27.4 ppm; HRMS (FAB) m/
z: [M + H]+ calcd for C16H13N2O3 281.0926; found: 281.0927.
(E)-N-(3-methoxyphenyl)-2-oxoindolin-3-imine oxide (3hG).
Flash column chromatography: 25−100% EtOAc/n-hexane; Yield:
42.8 mg, 80%; reddish-orange solid; mp 195−196 °C; 1H NMR (500
MHz, DMSO-d6) δ 10.75 (s, 1H), 8.26 (d, J = 7.6 Hz, 1H), 7.44−
7.38 (m, 2H), 7.19−7.17 (m, 1H), 7.14−7.03 (m, 3H), 6.90 (d, J =
7.8 Hz, 1H), 3.79 (s, 3H). ppm; 13C{1H} NMR (125 MHz, DMSO-
d6) δ 160.3, 159.7, 147.7, 141.5, 135.0, 132.8, 130.2, 124.6, 122.3,
118.8, 116.4, 110.3, 110.1, 56.0 ppm; HRMS (FAB) m/z: [M + H]+
calcd for C15H13N2O3 269.0926; found: 269.0928.
(E)-N-(3-(ethoxycarbonyl)phenyl)-2-oxoindolin-3-imine oxide
(3hH). Flash column chromatography: 25−100% EtOAc/n-hexane;
Yield: 49.6 mg, 80%; reddish-orange solid; mp 195−196 °C; 1H
NMR (500 MHz, DMSO-d6) δ 10.80 (s, 1H), 8.27 (d, J = 7.6 Hz,
1H), 8.15−8.07 (m, 2H), 7.92−7.86 (m, 1H), 7.68 (t, J = 7.9 Hz,
1H), 7.42 (t, J = 7.8 Hz, 1H), 7.09 (t, J = 7.6 Hz, 1H), 6.92 (d, J = 7.8
Hz, 1H), 4.35 (q, J = 7.1 Hz, 2H), 1.34 (t, J = 7.1 Hz, 3H) ppm;
13C{1H} NMR (125 MHz, DMSO-d6) δ 164.8, 160.2, 146.5, 141.3,
(Z)-N,1-Diphenylmethanimine oxide (3kA). Flash column chro-
matography: 10−25% EtOAc/n-hexane; Yield: 9.9 mg, 25%; yellow
1
solid; mp 104−106 °C; H NMR (500 MHz, CDCl3) δ 8.43−8.37
(m, 2H), 7.93 (s, 1H), 7.78 (dd, J = 7.6, 2.1 Hz, 2H), 7.48 (dt, J = 6.4,
3.2 Hz, 6H) ppm; 13C{1H} NMR (125 MHz, CDCl3) δ 149.1, 134.7,
131.0, 130.7, 129.9, 129.2, 129.1, 128.7, 121.8 ppm; HRMS (FAB)
m/z: [M + H]+ calcd for C13H12NO 198.0919; found: 198.0920.
(Z)-1-(4-Nitrophenyl)-N-phenylmethanimine oxide (3lA). Flash
column chromatography: 10−25% EtOAc/n-hexane; Yield: 27.6 mg,
57%; yellow solid; mp 175−176 °C; 1H NMR (500 MHz, CDCl3) δ
8.56 (d, J = 9.0 Hz, 2H), 8.31 (d, J = 9.0 Hz, 2H), 8.08 (s, 1H), 7.83−
7.75 (m, 2H), 7.56−7.48 (m, 3H) ppm; 13C{1H} NMR (125 MHz,
CDCl3) δ 148.9, 148.0, 136.2, 132.3, 130.7, 129.4, 129.2, 123.9, 121.7
ppm; HRMS (FAB) m/z: [M + H]+ calcd for C13H11N2O3 243.0770;
found: 243.0775.
(Z)-1-(3-Fluoro-4-nitrophenyl)-N-phenylmethanimine oxide
(3mA). Flash column chromatography: 10−25% EtOAc/n-hexane;
1
Yield: 44.2 mg, 85%; yellow solid; mp 160−161 °C; H NMR (500
MHz, CDCl3) δ 8.73 (dd, J = 12.8, 1.7 Hz, 1H), 8.14 (t, J = 8.1 Hz,
1H), 8.06 (s, 1H), 7.95 (d, J = 8.9 Hz, 1H), 7.81−7.74 (m, 2H),
7.57−7.49 (m, 3H) ppm; 13C{1H} NMR (125 MHz, CDCl3) δ 155.7
(d, JCF = 264.1 Hz), 148.8, 137.3 (d, JCF = 9.4 Hz), 137.1 (d, JCF = 8.5
Hz), 131.2 (d, JCF = 1.5 Hz), 131.0, 129.5, 126.2 (d, JCF = 2.4 Hz),
124.6 (d, JCF = 4.0 Hz), 121.7, 117.4 (d, JCF = 24.7 Hz) ppm; HRMS
(FAB) m/z: [M + H]+ calcd for C13H10FN2O3 261.0675; found:
261.0679.
135.1, 132.7, 130.8, 129.6, 128.9, 124.8, 124.5, 122.0, 118.3, 112.3,
110.0, 61.3, 14.2 ppm; HRMS (FAB) m/z: [M + H]+ calcd for
C17H15N2O4 311.1032; found: 311.1027.
(E)-N-(3-acetylphenyl)-2-oxoindolin-3-imine oxide (3hI). Flash
column chromatography: 25−100% EtOAc/n-hexane; Yield: 46.0 mg,
82%; orange solid; mp 196−197 °C; 1H NMR (500 MHz, DMSO-d6)
δ 10.80 (s, 1H), 8.28 (d, J = 7.6 Hz, 1H), 8.19−8.14 (m, 1H), 8.11 (d,
J = 7.8 Hz, 1H), 7.90−7.84 (m, 1H), 7.68 (t, J = 7.9 Hz, 1H), 7.42 (t,
J = 7.7 Hz, 1H), 7.09 (t, J = 7.7 Hz, 1H), 6.92 (d, J = 7.8 Hz, 1H),
2.62 (s, 3H) ppm; 13C{1H} NMR (125 MHz, DMSO-d6) δ 197.5,
160.6, 146.9, 141.6, 137.8, 135.4, 133.1, 130.1, 129.9, 129.1, 124.8,
124.4, 122.4, 118.7, 110.4, 27.3 ppm; HRMS (FAB) m/z: [M + H]+
calcd for C16H13N2O3 281.0926; found: 281.0929.
(E)-N-(4-(Dimethylamino)phenyl)-2-oxoindolin-3-imine oxide
(3hB). Flash column chromatography: 25−100% EtOAc/n-hexane;
Yield: 50.1 mg, 89%; maroon solid; mp 201−202 °C; 1H NMR (500
MHz, DMSO-d6) δ 10.68 (s, 1H), 8.24 (d, J = 7.6 Hz, 1H), 7.44 (d, J
= 8.6 Hz, 2H), 7.34 (t, J = 7.7 Hz, 1H), 7.02 (t, J = 7.6 Hz, 1H), 6.87
(d, J = 7.8 Hz, 1H), 6.70 (d, J = 8.6 Hz, 2H), 3.01 (s, 6H) ppm;
13C{1H} NMR (125 MHz, DMSO-d6) δ 160.7, 152.2, 140.7, 135.8,
133.1, 131.8, 126.0, 124.1, 122.0, 119.9, 110.9, 110.0, 40.3 ppm;
HRMS (FAB) m/z: [M + H]+ calcd for C16H16N3O2 282.1243;
found: 282.1248.
(E)-N-(2-Bromophenyl)-2-oxoindolin-3-imine oxide (3hJ). Flash
column chromatography: 25−100% EtOAc/n-hexane; Yield: 40.6 mg,
64%; orange solid; mp 197−199 °C; 1H NMR (500 MHz, DMSO-d6)
δ 10.84 (s, 1H), 8.27 (d, J = 7.6 Hz, 1H), 7.79 (d, J = 7.9 Hz, 1H),
7.62 (dd, J = 7.8, 1.6 Hz, 1H), 7.58−7.53 (m, 1H), 7.49−7.42 (m,
2H), 7.10 (t, J = 7.6 Hz, 1H), 6.93 (d, J = 7.9 Hz, 1H) ppm; 13C{1H}
NMR (125 MHz, DMSO-d6) δ 160.2, 146.1, 141.9, 135.7, 133.6,
133.4, 131.8, 129.4, 126.4, 125.0, 122.6, 117.9, 116.2, 110.6 ppm;
HRMS (FAB) m/z: [M + H]+ calcd for C14H10BrN2O2 316.9926;
found: 316.9921.
(E)-N-(4-Methoxyphenyl)-2-oxoindolin-3-imine oxide (3hC).
Flash column chromatography: 25−100% EtOAc/n-hexane; Yield:
1
47.8 mg, 89%; orange solid; mp 200−201 °C; H NMR (500 MHz,
DMSO-d6) δ 10.73 (s, 1H), 8.29−8.24 (m, 1H), 7.56−7.53 (m, 2H),
7.38 (td, J = 7.7, 1.3 Hz, 1H), 7.06−7.00 (m, 3H), 6.89 (d, J = 7.7 Hz,
1H), 3.84 (s, 3H) ppm; 13C{1H} NMR (125 MHz, DMSO-d6) δ
161.0, 160.6, 141.2, 140.1, 134.6, 132.5, 126.2, 124.5, 122.2, 119.2,
114.1, 110.2, 56.0 ppm; HRMS (FAB) m/z: [M + H]+ calcd for
C15H13N2O3 269.0926; found: 269.0930.
(Z)-N-tert-Butyl-1-(4-nitrophenyl)methanimine oxide (3lK). Flash
column chromatography: 10−25% EtOAc/n-hexane; Yield: 25.3 mg,
1
52%; yellow solid; mp 133−135 °C; H NMR (500 MHz, CDCl3) δ
(E)-N-(4-Bromophenyl)-2-oxoindolin-3-imine oxide (3hD). Flash
column chromatography: 25−100% EtOAc/n-hexane; Yield: 62.8 mg,
99%; orange solid; mp 201−203 °C; 1H NMR (500 MHz, DMSO-d6)
δ 10.79 (s, 1H), 8.25 (d, J = 7.6 Hz, 1H), 7.76−7.68 (m, 2H), 7.60−
7.53 (m, 2H), 7.41 (td, J = 7.7, 1.3 Hz, 1H), 7.07 (td, J = 7.6, 1.0 Hz,
1H), 6.89 (d, J = 7.8 Hz, 1H) ppm; 13C{1H} NMR (125 MHz,
DMSO-d6) δ 160.5, 145.8, 141.6, 135.3, 133.0, 132.3, 126.7, 124.7,
123.8, 122.4, 118.8, 110.4 ppm; HRMS (FAB) m/z: [M + H]+ calcd
for C14H8BrN2O2 316.9926; found: 316.9916.
8.48−8.41 (m, 2H), 8.29−8.23 (m, 2H), 7.70 (s, 1H), 1.64 (s, 9H)
ppm; 13C{1H} NMR (125 MHz, CDCl3) δ 147.6, 136.7, 128.9, 127.9,
123.7, 72.4, 28.3 ppm; HRMS (FAB) m/z: [M + H]+ calcd for
C11H15N2O3 223.1083; found: 223.1085.
(Z)-N-tert-Butyl-1-(3-fluoro-4-nitrophenyl)methanimine oxide
(3mK). Flash column chromatography: 10−25% EtOAc/n-hexane;
1
Yield: 34.2 mg, 71%; pale yellow solid; mp 137−138 °C; H NMR
(500 MHz, CDCl3) δ 8.66 (dd, J = 13.1, 1.8 Hz, 1H), 8.08 (t, J = 8.2
Hz, 1H), 7.84−7.79 (m, 1H), 7.68 (s, 1H), 1.63 (s, 9H) ppm;
13C{1H} NMR (125 MHz, CDCl3) δ 155.7 (d, JCF = 263.5 Hz), 137.9
(d, JCF = 9.6 Hz), 136.5 (d, JCF = 8.3 Hz), 127.0 (d, JCF = 1.6 Hz),
125.9 (d, JCF = 2.4 Hz), 124.3 (d, JCF = 3.9 Hz), 117.1 (d, JCF = 24.7
Hz), 72.8, 28.3 ppm; HRMS (FAB) m/z: [M + H]+ calcd for
C11H14N2O3 241.0944; found: 241.0991.
(E)-N-(4-(Ethoxycarbonyl)phenyl)-2-oxoindolin-3-imine oxide
(3hE). Flash column chromatography: 25−100% EtOAc/n-hexane;
1
Yield: 62.1 mg, 99%; orange solid; mp 200−201 °C; H NMR (500
MHz, DMSO-d6) δ 10.82 (s, 1H), 8.27 (d, J = 7.6 Hz, 1H), 8.08 (d, J
= 8.5 Hz, 2H), 7.74 (d, J = 8.5 Hz, 2H), 7.41 (t, J = 7.8 Hz, 1H), 7.08
(t, J = 7.6 Hz, 1H), 6.91 (d, J = 7.8 Hz, 1H), 4.37 (q, J = 7.1 Hz, 2H),
1.36 (t, J = 7.1 Hz, 3H) ppm; 13C{1H} NMR (125 MHz, DMSO-d6)
δ 165.3, 160.5, 149.8, 141.7, 135.5, 133.1, 131.7, 130.3, 125.0, 124.8,
(Z)-N-tert-Butyl-1-(2-nitrophenyl)methanimine oxide (3nK).
Flash column chromatography: 10−25% EtOAc/n-hexane; Yield:
6348
https://doi.org/10.1021/acs.joc.1c00158
J. Org. Chem. 2021, 86, 6343−6350

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
25.3 mg, 62%; yellow oil; 1H NMR (500 MHz, CDCl3) δ 9.00 (d, J =
8.0 Hz, 1H), 8.18 (s, 1H), 8.03 (dd, J = 8.2, 1.3 Hz, 1H), 7.68 (t, J =
7.7 Hz, 1H), 7.54−7.47 (m, 1H), 1.62 (s, 9H) ppm; 13C{1H} NMR
(125 MHz, CDCl3) δ 147.6, 133.2, 129.7, 129.6, 125.1, 124.8, 124.2,
72.4, 28.2 ppm; HRMS (FAB) m/z: [M + H]+ calcd for C11H15N2O3
223.1083; found: 223.1085.
Jee Eun Hong − College of Pharmacy, Inje Institute of
Pharmaceutical Sciences and Research, Inje University,
Gyeongnam 50834, Republic of Korea
Jae-Hwan Kwak − College of Pharmacy, Kyungsung
University, Busan 48434, Republic of Korea; orcid.org/
0000-0003-2020-699X
(Z)-N-tert-Butyl-1-(4-cyanophenyl)methanimine oxide (3oK).
Flash column chromatography: 10−25% EtOAc/n-hexane; Yield:
28.8 mg, 71%; off-white solid; mp 152−154 °C; 1H NMR (500 MHz,
CDCl3) δ 8.38 (d, J = 8.3 Hz, 2H), 7.68 (d, J = 8.3 Hz, 2H), 7.63 (s,
1H), 1.63 (s, 9H) ppm; 13C{1H} NMR (125 MHz, CDCl3) δ 134.9,
132.2, 128.6, 127.0, 118.6, 112.6, 72.1, 28.3 ppm; HRMS (FAB) m/z:
[M + H]+ calcd for C12H15N2O 203.1184; found: 203.1184.
1,3-Diethoxy-1,3-dioxo-N-phenylpropan-2-imine oxide (3rA).
Flash column chromatography: 10−30% EtOAc/n-hexane; Yield:
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.1c00158
Author Contributions
Y.J. and J.E.H. contributed equally to this work. The
manuscript was written through the contribution of all authors.
All authors have given approval for the submission of the
manuscript.
1
30.9 mg, 58%; yellow oil; H NMR (500 MHz, CDCl3) δ 7.53−7.49
(m, 1H), 7.49−7.39 (m, 4H), 4.45 (q, J = 7.1 Hz, 2H), 4.12 (q, J =
7.1 Hz, 2H), 1.40 (t, J = 7.1 Hz, 3H), 1.12 (t, J = 7.1 Hz, 3H) ppm;
13C{1H} NMR (125 MHz, CDCl3) δ 160.3, 158.7, 147.2, 130.9,
Notes
The authors declare no competing financial interest.
129.1, 123.0, 62.7, 62.3, 14.0, 13.7 ppm; HRMS (FAB) m/z: [M +
ACKNOWLEDGMENTS
H]+ calcd for C13H16NO5 266.1028; found: 266.1029.
■
This work was supported by the Basic Science Research
Program (NRF-2016R1D1A1B04930774) of the Ministry of
Education and the Bio-Synergy Research Project (NRF-
2021M3A9C4000960) of the Ministry of Science, ICT and
Future Planning through the National Research Foundation of
Korea (NRF).
5-Ethyl 3-methyl 2,3-diphenylisoxazolidine-3,5-dicarboxylate
(5). To a solution of 1 (0.4 mmol) in DMA (2.0 mL) were added
the catalyst (4.9 mg, 0.04 mmol), Li2CO3 (59.1 mg, 0.8 mmol), and
2A (0.4 mmol) at room temperature. After stirring for 24 h, ethyl
acrylate (85 μL, 0.8 mmol) was added. The reaction mixture was
heated to 80 °C using an oil bath, stirred for additional 16 h, diluted
with EtOAc (30 mL), and washed with brine (30 mL × 3). The
extract was dried over anhydrous MgSO4. After filtration of the solid,
the solvent in the filtrate was removed in vacuo, and the residue was
purified by silica gel column chromatography (10−25% EtOAc/n-
hexane) to give the corresponding isoxazolidine 5 as a 1.5:1 mixture
of diastereomers. Yield: 88.1 mg, 62%; gummy solid. Diastereomer A
REFERENCES
■
(1) (a) Schmid-Elsaesser, R.; Hungerhuber, E.; Zausinger, S.;
Baethmann, A.; Reulen, H.-J. Neuroprotective effects of the novel
brain-penetrating antioxidant U-101033E and the spin-trapping agent
α-phenyl-N-tert-butyl nitrone (PBN). Exp. Brain Res. 2000, 130, 60−
66. (b) Shuaib, A.; Lees, K. R.; Lyden, P.; Grotta, J.; Davalos, A.;
Davis, S. M.; Diener, H.-C.; Ashwood, T.; Wasiewski, W. W.;
Emeribe, U. NXY-059 for the Treatment of Acute Ischemic Stroke. N.
Engl. J. Med. 2007, 357, 562−571. (c) Matias, A. C.; Biazolla, G.;
Cerchiaro, G.; Keppler, A. F. α-Aryl-N-aryl nitrones: Synthesis and
screening of a new scaffold for cellular protection against an oxidative
toxic stimulus. Bioorg. Med. Chem. 2016, 24, 232−239. (d) Oliveira,
C.; Bagetta, D.; Cagide, F.; Teixeira, J.; Amorim, R.; Silva, T.; Garrido,
1
(major): H NMR (500 MHz, CDCl3) δ 7.86−6.92(m, 10H), 4.88
(dd, J = 8.8, 5.0 Hz, 1H), 4.15 (q, J = 7.1 Hz, 2H), 3.67 (dd, J = 12.8,
8.8 Hz, 1H), 3.46 (s, 3H), 2.95 (dd, J = 12.8, 4.9 Hz, 1H), 1.20 (t, J =
1
7.1 Hz, 3H) ppm. Diastereomer B (minor): H NMR (500 MHz,
CDCl3) δ 7.86−6.92 (m, 10H), 4.76 (dd, J = 8.4, 6.9 Hz, 1H), 4.31−
4.23 (m, 2H), 3.58 (dd, J = 12.7, 6.9 Hz, 1H), 3.51 (s, 3H), 2.97 (dd,
J = 12.8, 8.4 Hz, 1H), 1.31 (d, J = 14.3 Hz, 3H) ppm; 13C{1H} NMR
(125 MHz, CDCl3) δ 170.9, 170.6, 170.5, 169.8, 147.0, 146.9, 138.8,
138.3, 138.1, 131.8, 129.1, 128.8, 128.5, 128.4, 128.2, 128.1, 128.1,
127.4, 127.4, 127.1, 124.5, 123.7, 123.1, 120.3, 119.0, 117.7, 78.0,
77.7, 74.8, 74.6, 61.6, 61.5, 52.5, 52.3, 47.7, 46.0, 14.2, 14.1 ppm;
HRMS (FAB) m/z: [M]+ calcd for C20H21NO5 355.1420; found:
355.1420.
J.; Remiao, F.; Uriarte, E.; Oliveira, P. J.; Alcaro, S.; Ortuso, F.;
̃
Borges, F. Benzoic acid-derived nitrones: A new class of potential
acetylcholinesterase inhibitors and neuroprotective agents. Eur. J.
Med. Chem. 2019, 174, 116−129. (e) Chamorro, B.; Diez-Iriepa, D.;
Merás-Sáiz, B.; Chioua, M.; García-Vieira, D.; Iriepa, I.; Hadjipavlou-
̀
Litina, D.; López-Munoz, F.; Martínez-Murillo, R.; Gonzalez-Nieto,
̃
ASSOCIATED CONTENT
■
D.; Fernández, I.; Marco-Contelles, J.; Oset-Gasque, M. J. Synthesis,
antioxidant properties and neuroprotection of α-phenyl-tert-butylni-
trone derived HomoBisNitrones in in vitro and in vivo ischemia
models. Sci. Rep. 2020, 10, No. 14150. (f) Marco-Contelles, J. Recent
Advances on Nitrones Design for Stroke Treatment. J. Med. Chem.
2020, 63, 13413−13427.
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.1c00158.
1H NMR and 13C{1H} NMR spectra for all products 3
and 5 (PDF)
(2) (a) Hamer, J.; Macaluso, A. Nitrones. Chem. Rev. 1964, 64, 473−
495. (b) Cardona, F.; Goti, A. The Discovery of Novel Metal-Induced
Reactions of Nitrones: Not Only Electrophiles and Reagents for [3 +
2] Cycloadditions. Angew. Chem., Int. Ed. 2005, 44, 7832−7835.
(c) Namitharan, K.; Pitchumani, K. Copper(I)-Catalyzed Three
Component Reaction of Sulfonyl Azide, Alkyne, and Nitrone
Cycloaddition/Rearrangement Cascades: A Novel One-Step Syn-
thesis of Imidazolidin-4-ones. Org. Lett. 2011, 13, 5728−5731.
(d) Murahashi, S.-I.; Imada, Y. Synthesis and Transformations of
Nitrones for Organic Synthesis. Chem. Rev. 2019, 119, 4684−4716.
(3) (a) Murray, R. W.; Singh, M. A Facile One-Step Synthesis of C-
Arylnitrones Using Dimethyldioxirane. J. Org. Chem. 1990, 55, 2954−
2957. (b) Matassini, C.; Parmeggiani, C.; Cardona, F.; Goti, A.
Oxidation of N,N-Disubstituted Hydroxylamines to Nitrones with
Hypervalent Iodine Reagents. Org. Lett. 2015, 17, 4082−4085.
(c) Nguyen, D.-V.; Prakash, P.; Gravel, E.; Doris, E. Triphenylbis-
AUTHOR INFORMATION
■
Corresponding Author
Yohan Park − College of Pharmacy, Inje Institute of
Pharmaceutical Sciences and Research, Inje University,
Gyeongnam 50834, Republic of Korea; orcid.org/0000-
0001-6844-2241; Phone: +82-55-320-3466;
Email: yohanpark@inje.ac.kr; Fax: +82-55-320-3940
Authors
Yeonghun Jung − College of Pharmacy, Inje Institute of
Pharmaceutical Sciences and Research, Inje University,
Gyeongnam 50834, Republic of Korea
6349
https://doi.org/10.1021/acs.joc.1c00158
J. Org. Chem. 2021, 86, 6343−6350

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
muth Carbonate-mediated Oxidation of Hydroxylamines to Nitrones
and in situ 1,3-Dipolar Cycloaddition. RSC Adv. 2016, 6, 89238−
89241. (d) Matassini, C.; Cardona, F. Oxidation of N,N-Disubstituted
Hydroxylamines to Nitrones: The Search for More Sustainable
Selective and Practical Stoichiometric Oxidants. Chimia 2017, 71,
558−561.
(4) (a) Colladon, M.; Scarso, A.; Strukul, G. Mild Catalytic
Oxidation of Secondary and Tertiary Amines to Nitrones and N-
Oxides with H2O2 Mediated by Pt(II) Catalysts. Green Chem. 2008,
10, 793−798. (b) Zonta, C.; Cazzola, E.; Mba, M.; Licini, G. C3-
Symmetric Titanium(IV) Triphenolate Amino Complexes for a Fast
and Effective Oxidation of Secondary Amines to Nitrones with
Hydrogen Peroxide. Adv. Synth. Catal. 2008, 350, 2503−2506.
(c) Forcato, M.; Mba, M.; Nugent, W. A.; Licini, G. Effective
Oxidation of Secondary Amines to Nitrones with Alkyl Hydro-
peroxides Catalysed by (Trialkanolaminato)titanium(IV) Complexes.
Eur. J. Org. Chem. 2010, 2010, 740−748.
(5) (a) Soldaini, G.; Cardona, F.; Goti, A. Catalytic Oxidation of
Imines Based on Methyltrioxorhenium/Urea Hydrogen Peroxide: A
Mild and Easy Chemo- and Regioselective Entry to Nitrones. Org.
Lett. 2007, 9, 473−476. (b) Cardona, F.; Bonanni, M.; Soldaini, G.;
Goti, A. One-Pot Synthesis of Nitrones from Primary Amines and
Aldehydes Catalyzed by Methyltrioxorhenium. ChemSusChem 2008,
1, 327−332. (c) Singh, B.; Jain, S. L.; Khatri, P. K.; Sain, B. Nafion
Supported Molybdenum Oxychloride: Recyclable Catalyst for One-
Pot Synthesis of Nitrones via Direct Condensation/Oxidation of
Primary Amines and Aldehydes Using UHP as Oxidant. Green Chem.
2009, 11, 1941−1944.
(6) (a) Cisneros, L.; Serna, P.; Corma, A. Selective Reductive
Coupling of Nitro Compounds with Aldehydes to Nitrones in H2
Using Carbon-Supported and -Decorated Platinum Nanoparticles.
Angew. Chem., Int. Ed. 2014, 53, 9306−9310. (b) Lin, C.-W.; Hong,
B.-C.; Chang, W.-C.; Lee, G.-H. A New Approach to Nitrones
through Cascade Reaction of Nitro Compounds Enabled by Visible
Light Photoredox Catalysis. Org. Lett. 2015, 17, 2314−2317. (c) Li,
X.; Zhang, B.; Tang, L.; Goh, T. W.; Qi, S.; Volkov, A.; Pei, Y.; Qi, Z.;
Tsung, C.-K.; Stanley, L.; Huang, W. Cooperative Multifunctional
Catalysts for Nitrone Synthesis: Platinum Nanoclusters in Amine-
Functionalized Metal−Organic Frameworks. Angew. Chem., Int. Ed.
2017, 56, 16371−16375.
(7) (a) Yang, H.-B.; Shi, M. Yb(NTf2)3-catalyzed [3 + 3]
cycloaddition between isatin ketonitrones and cyclopropanes to
construct novel spiro[tetrahydro-1,2-oxazine]oxindoles. Org. Biomol.
Chem. 2012, 10, 8236−8243. (b) Mo, D.-L.; Anderson, L. L. Copper-
Catalyzed Rearrangement of N-Aryl Nitrones into Epoxyketimines.
Angew. Chem., Int. Ed. 2013, 52, 6722−6725. (c) Mo, X.-L.; Chen, C.-
H.; Liang, C.; Mo, D.-L. Copper-Catalyzed Carbonyl Group
Controlled Coupling of Isatin Oximes with Arylboronic Acids to
Prepare N-Aryloxindole Nitrones. Eur. J. Org. Chem. 2018, 2018,
150−159. (d) Ma, X.-P.; Shi, W.-M.; Mo, X.-L.; Li, X.-H.; Li, L.-G.;
Pan, C.-X.; Chen, B.; Su, G.-F.; Mo, D.-L. Synthesis of α,β-
Unsaturated N-Aryl Ketonitrones from Oximes and Diaryliodonium
Salts: Observation of a Metal-Free N-Arylation Process. J. Org. Chem.
2015, 80, 10098−10107. (e) Wu, S.-Y.; Ma, X.-P.; Liang, C.; Mo, D.-
L. Synthesis of N-Aryl Oxindole Nitrones through a Metal-Free
Selective N-Arylation Process. J. Org. Chem. 2017, 82, 3232−3238.
(f) Shi, W.-M.; Ma, X.-P.; Su, G.-F.; Mo, D.-L. New developments of
ketonitrones in organic synthesis. Org. Chem. Front. 2016, 3, 116−
130.
Commun. 2014, 50, 15864−15866. (c) Zhang, Y.-H.; Wu, M.-Y.;
Huang, W.-C. Silica gel-promoted practical synthesis of oxindole−
nitrones from diazooxindoles and nitrosoarenes under solvent-free
conditions. RSC Adv. 2015, 5, 105825−105828. (d) Fraboni, A. J.;
Brenner-Moyer, S. E. Dienamine-Catalyzed Nitrone Formation via
Redox Reaction. Org. Lett. 2016, 18, 2146−2149. (e) Choi, M.; Viji,
M.; Kim, D.; Lee, Y. H.; Sim, J.; Kwak, Y.-S.; Lee, K.; Lee, H.; Jung, J.-
K. Metal-free approach for the L-proline mediated synthesis of
nitrones from nitrosobenzene. Tetrahedron 2018, 74, 4182−4187.
(f) Rodrigo, E.; Alonso, I.; Cid, M. B. A Protocol To Transform
Sulfones into Nitrones and Aldehydes. Org. Lett. 2018, 20, 5789−
5793. (g) Liu, T.; Liu, Z.; Liu, Z.; Hu, D.; Wang, Y. Coupling of N-
Nosylhydrazones with Nitrosoarenes: Transition-Metal-Free Ap-
proach to (Z)-N-Arylnitrones. Synthesis 2018, 50, 1728−1736.
(h) Volpe, C.; Meninno, S.; Roselli, A.; Mancinelli, M.; Mazzanti,
A.; Lattanzi, A. Nitrone/Imine Selectivity Switch in Base-Catalysed
Reaction of Aryl Acetic Acid Esters with Nitrosoarenes: Joint
Experimental and Computational Study. Adv. Synth. Catal. 2020,
362, 5457−5466.
(10) Kröhnke, F. Syntheses Using Pyridinium Salts (IV). Angew.
Chem., Int. Ed. 1963, 2, 380−393.
(11) (a) Li, X.; Wu, S.; Chen, S.; Lai, Z.; Luo, H.-B.; Sheng, C. One-
Pot Synthesis of Deuterated Aldehydes from Arylmethyl Halides. Org.
Lett. 2018, 20, 1712−1715. (b) Faisal, M.; Hussain, S.; Haider, A.;
Saeed, A.; Larik, F. A. Assessing the effectiveness of oxidative
approaches for the synthesis of aldehydes and ketones from oxidation
of iodomethyl group. Chem. Pap. 2019, 73, 1053−1067.
(12) (a) Wang, Q.-F.; Song, X.-K.; Chen, J.; Yan, C.-G. Pyridinium
Ylide-Assisted One-Pot Two-Step Tandem Synthesis of Polysub-
stituted Cyclopropanes. J. Comb. Chem. 2009, 11, 1007−1010.
(b) Kanomata, N.; Sakaguchi, R.; Sekine, K.; Yamashita, S.; Tanaka,
H. Enantioselective Cyclopropanation Reactions with Planar-Chiral
Pyridinium Ylides: A Substituent Effect and a Remote Steric Effect.
Adv. Synth. Catal. 2010, 352, 2966−2978. (c) Allgäuer, D. S.; Mayer,
P.; Mayr, H. Nucleophilicity Parameters of Pyridinium Ylides and
Their Use in Mechanistic Analyses. J. Am. Chem. Soc. 2013, 135,
15216−15224. (d) Bonte, S.; Ghinea, I. O.; Dinica, R.; Baussanne, I.;
Demeunynck, M. Investigation of the Pyridinium Ylide−Alkyne
Cycloaddition as a Fluorogenic Coupling Reaction. Molecules 2016,
21, No. 332.
(13) Kajita, H.; Togni, A. A Oxidative Bromination of (Hetero)
Arenes in the TMSBr/DMSO System: A Non-Aqueous Procedure
Facilitates Synthetic Strategies. ChemistrySelect 2017, 2, 1117−1121.
(14) (a) Priewisch, B.; Ruck-Braun, K. Efficient Preparation of
̈
Nitrosoarenes for the Synthesis of Azobenzenes. J. Org. Chem. 2005,
70, 2350−2352. (b) Blackburn, O. A.; Coe, B. J.; Helliwell, M.
Tetrapalladium(II) Bisazobenzene and Azoazoxybenzene Complexes:
Syntheses, Electronic Structures, and Optical Properties. Organo-
metallics 2011, 30, 4910−4923.
(8) Jung, Y.; Hong, J. E.; Baek, S. T.; Hong, S.; Kwak, J.-H.; Park, Y.
4-Dimethylaminopyridine-Catalyzed Metal-Free Aerobic Oxidation of
Aryl α-Halo Esters to Aryl α-Keto Esters. ACS Omega 2020, 5,
22951−22957.
(9) (a) Chavannavar, A. P.; Oliver, A. G.; Ashfeld, B. L. An
Umpolung Approach toward N-Aryl Nitrone Construction: A
Phosphine-Mediated Addition of 1,2-Dicarbonyls to Nitroso Electro-
philes. Chem. Commun. 2014, 50, 10853−10856. (b) Singh, R. R.;
Liu, R.-S. Gold-Catalyzed 1,2-Iminonitronation of Electron-Deficient
Alkynes with Nitrosoarenes to Afford α-Imidoyl Nitrones. Chem.
6350
https://doi.org/10.1021/acs.joc.1c00158
J. Org. Chem. 2021, 86, 6343−6350