Nitrone Formation by Reaction of an Enolate with a Nitro Group

Article abstract of DOI:10.1021/acs.orglett.1c00603

Ketones with a 2-nitrophenyl group at the α-position were treated with sodium hydroxide in methanol at 60 °C. Under these conditions, enolates derived from the ketones intramolecularly reacted with the nitro group to form a variety of nitrones. Additional experimental results, including the unexpected isolation of N-hydroxyindolinone as a byproduct, led to a proposed reaction mechanism, occurring via an α-hydroxyketone. The resultant nitrones underwent inter- and intramolecular 1,3-dipolar cycloaddition with olefins to afford polycyclic isoxazolidines.

Full text of DOI:10.1021/acs.orglett.1c00603

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Letter
Nitrone Formation by Reaction of an Enolate with a Nitro Group
Hiroaki Shimizu, Kohei Yoshinaga, and Satoshi Yokoshima*
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ABSTRACT: Ketones with a 2-nitrophenyl group at the α-position were treated with
sodium hydroxide in methanol at 60 °C. Under these conditions, enolates derived
from the ketones intramolecularly reacted with the nitro group to form a variety of
nitrones. Additional experimental results, including the unexpected isolation of N-
hydroxyindolinone as a byproduct, led to a proposed reaction mechanism, occurring
via an α-hydroxyketone. The resultant nitrones underwent inter- and intramolecular 1,3-dipolar cycloaddition with olefins to afford
polycyclic isoxazolidines.
ketone can be almost equally deprotonated.3 The production
n our synthesis of aurachins, we used a reaction that
Iconverts ketones bearing a 2-nitrophenyl group at the α-
of the corresponding 3-hydroxyquinoline N-oxide in 49% yield,
even by treatment of the substrate with 0.5 equiv of sodium
tert-butoxide, indicated that the former mechanism via the
reaction of enolates with a nitro group to form nitrones seems
more probable.4,5 To support the reaction mechanism, and
being interested in the reactivity of the nitrones thus formed,
we have continued our investigation of the reaction. Herein we
disclose the formation of nitrones by the reaction between an
enolate and a nitro group. The resulting nitrones were
subjected to 1,3-dipolar cycloaddition.6
position into 3-hydroxyquinoline N-oxides by treatment with
sodium tert-butoxide in dimethyl sulfoxide (Scheme 1).1
Although the precise mechanism of the reaction has not
been fully elucidated, a reaction of enolate 2 to form nitrone 3
or an electrocyclic reaction of dianion 5 is assumed to
functionalize the α-position of the ketone moiety.2 Deuteration
experiments demonstrated that both of the α-positions of the
Scheme 1. Total Synthesis of Aurachins via the Formation
For the investigation, we designed ketone 11a as the
substrate because it has no benzylic proton and has a benzylic
carbon that is a quaternary carbon. This avoided tautomeriza-
tion for the formation of 3-hydroxyquinoline N-oxide. The
ketone was prepared according to Scheme 2. Ester 7 was
sequentially alkylated to construct the quaternary carbon. The
resulting ester 8a was converted into aldehyde 9a via a
sequence involving reduction with diisobutylaluminum hydride
(DIBAL) and oxidation with pyridinium chlorochromate
(PCC). Attempted reactions of aldehyde 9a with organometal
reagents, including n-butyllithium, ethylmagnesium bromide,
ethynylmagnesium bromide, diethylzinc, and so on, resulted in
decomposition of the substrate due to the unwanted reaction
of the nitro group. Despite this, a reaction with an enolate
derived from tert-butyl propionate afforded β-hydroxy ester,7
which was oxidized into β-ketoester 10a. Cleavage of the tert-
butyl group with trifluoroacetic acid, followed by decarbox-
ylation under thermal conditions, gave the requisite ketone
11a.8
of Quinoline N-Oxide
Received: February 19, 2021
Published: March 16, 2021
https://dx.doi.org/10.1021/acs.orglett.1c00603
© 2021 American Chemical Society
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hydroxyindolinone 13 in 65% yield (entry 8). By diluting the
reaction to 1.25 mM, the product ratio was improved to afford
nitrone 12a and indolinone 13 in 71 and 17% yield,
respectively (entry 9), whereas further dilution (0.13 mM)
resulted in a sluggish reaction (entry 10). Replacing methanol
with other alcohols, such as ethanol or 2-propanol, resulted in
the selective production of indolinone 13 (entries 11 and 12).
Of the several bases we tried, sodium hydroxide gave the best
results (entries 13 and 14); therefore, we designated the
conditions in entry 9 to be the optimal conditions and applied
them to other substrates.
Scheme 2. Preparation of the Substrate
Applying the optimal conditions to a variety of substrates
produced the corresponding nitrones in moderate to good
yields (Scheme 3). The size of the substituents on the benzylic
position affected the reaction. Whereas a reaction of the
dimethyl derivative produced nitrone 12b in 42% yield,
substrates with bulkier substituents, which might bring the
enolate and the nitro group close together, resulted in better
yields (12c and 12d). A reaction of the substrate with a 3-
buten-1-yl group afforded nitrone 12e in 35% yield,
accompanied by the production of isoxazolidine 15e in 42%
yield via the intramolecular cycloaddition of the nitrone with
the butenyl group (vide infra). Interestingly, a reaction of
methyl ketone (R3 = H) did not give the corresponding
nitrone 12f, and the substrate was recovered in 52% yield.
Substrates with an electron-withdrawing group at the α-
position of the ketone could also be converted into nitrones
12g and 12h in 20 and 38% yield, respectively. The low yields
might result from the high reactivity of the resulting nitrones.
The intermolecular cycloaddition of nitrone 12b with a
variety of olefins regioselectively occurred by heating in
toluene to 80 or 100 °C to afford isoxazolidine 14m−o with
high diastereoselectivity (Table 2). The stereochemistry of
each major product was exo, which was confirmed with nuclear
Overhauser effect spectroscopy (NOESY) experiments. The
With the requisite ketone in hand, we attempted to convert
it into the nitrone. Subjecting ketone 11a to the conditions of
our synthesis of 3-hydroxyquinoline N-oxide with sodium tert-
butoxide in dimethyl sulfoxide at room temperature1 resulted
in decomposition of the substrate, and the desired nitrone 12a
was not obtained (Table 1, entry 1). Replacement of the
solvent with N,N-dimethylformamide or replacement of the
base with potassium tert-butoxide produced the same result
(entries 2−4). Upon treatment with sodium hydride in
tetrahydrofuran or with potassium carbonate in dimethyl
sulfoxide, no reaction was observed, and the ketone was
recovered (entries 5 and 6). When 1 equiv of sodium
hydroxide was used in methanol at room temperature, a trace
amount of nitrone 12a was detected in the reaction mixture
(entry 7). Increasing the amount of sodium hydroxide and
raising the reaction temperature to 60 °C produced nitrone
12a in 8% yield, accompanied by the formation of N-
Table 1. Optimization of Conditions for Nitrone Formation
yield (%)
a
entry
base
X
solvent
conc (mM)
T (°C)
12a
13
b
1
NaOt-Bu
NaOt-Bu
KOt-Bu
KOt-Bu
NaH
K2CO3
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
LiOH
1.5
1.5
1.5
1.5
1.5
2.0
1.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
DMSO
DMF
DMSO
DMF
10−15
10−15
10−15
10−15
10−15
10−15
10−15
12.5
1.25
0.13
1.25
1.25
rt
rt
rt
rt
rt
rt
rt
60
60
60
60
60
60
60
−
−
−
−
−
−
trace
8
71
trace
trace
−
47
39
−
−
−
−
−
b
2
b
3
b
4
c
5
THF
c
6
DMSO
MeOH
MeOH
MeOH
MeOH
EtOH
i-PrOH
MeOH
MeOH
−
−
d
7
e
8
65
17
−
44
32
23
23
e
9
e
10
11
12
13
e
e
e
1.25
1.25
e
14
KOH
a
b
c
d
Concentration of the substrate 11a. Decomposition of the substrate 11a was observed. No reaction after 24 h. Reaction was conducted for 24
e
h. Reaction was conducted for 12 h.
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Scheme 3. Nitrone Formation
Scheme 4. Intramolecular Cycloaddition of Nitrones
a
Intramolecular cycloaddition also occurred under the conditions to
b
Scheme 5. One-Pot Conversion of Ketone 11e into
Isoxazolidine 15e
give isoxazolidine 15e in 42% yield. 52% of the starting material was
recovered. 0.5 equiv of NaOH was used, and the reaction was
conducted at 50 °C for 5 h. Reaction was conducted at 60 °C for 30
min.
c
d
Table 2. Intermolecular Cycloaddition of Nitrone 12b
explain our results. Indeed, reactions of carbanions with a nitro
group commonly occur on the oxygen atom of the nitro group,
through ionic or radical mechanisms, to form a C−O
bond.9−11 In our case, the intramolecular addition of an
enolate to the nitro group would occur to form oxazepane 17
(Scheme 6). The resulting oxazepane ring would be cleaved by
electron donation from the other oxygen atom to afford nitroso
compound 18. A Cannizzaro-like hydride shift from the
secondary alcohol moiety to the nitroso group (shown by red
entry
R
temp (°C)
product
yield (%)
exo/endo
1
2
3
CO2Me
On-Bu
(CH2)2OH
80
80
100
14m
14n
14o
83
73
73
1.3:1
>20:1
9:1
intramolecular cycloaddition of nitrone 12a, which had a
methyl group and an allyl group at the benzyl position, did not
proceed by heating to 150 °C (Scheme 4). Reactions of
nitrone 12c or 12d, which had an allyl or a phenyl group,
respectively, instead of the methyl group of 12a, gave the
corresponding isoxazolidine 15c or 15d. An electron-with-
drawing group connected to the nitrone, such as an ester
moiety in 12g or a 2-pyridyl group in 12h, increased the
reactivity for the cycloaddition, and upon heating in toluene at
110 °C, isoxazolidines 15g and 15h were obtained in 56 and
89% yield, respectively. Cycloaddition of 12e, which had an
allyl group and a 3-buten-1-yl group, selectively occurred on
the butenyl group at a lower temperature (80 °C) to furnish
15e in 91% yield. In addition, the formation of nitrone 12e and
its cycloaddition could be conducted in a one-pot process.
Thus the treatment of 11e with sodium hydroxide in methanol
at 65 °C for 24 h gave 15e in 50% yield (Scheme 5).
Scheme 6. Proposed Reaction Mechanisms
A reaction mechanism for the nitrone formation is proposed
as follows. For the mechanism of reactions between an enolate
and a nitro group, addition to the nitrogen atom of the nitro
group have been proposed; however, we thought that a
mechanism via addition to the oxygen atom could adequately
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arrows) would form diketone 19,12 which would undergo
condensation between a carbonyl group and the hydroxylami-
no group to produce nitrone 12.13
a
Scheme 7. Explanation of Concentration Dependence
The nitroso intermediate can be connected to the formation
of N-hydroxyindolinone 13 via zwitterionic structure 20.14
Thus the addition of the nitrogen atom of the nitroso group to
the carbonyl group (shown by blue arrows) followed by
cleavage of the C−C σ-bond between CCO and Cα, leading to
the elimination of an aldehyde, would form indolinone 13 after
protonation.15 Using density functional theory (DFT)
calculations, we obtained the structure corresponding to 20
as a transition state, not an intermediate (Figure 1a).
Figure 1. Structures of transition state in the conversion of 18 into
21. Interatomic distances are given in angstroms.
Observation of the calculated structure (TS1) shows that the
addition of the nitrogen atom to the carbonyl group and the
cleavage of the C−C σ-bond occurred concurrently (Figure
1b). The cleavage of the C−C σ-bond is induced by electron
donation from the alkoxide anion, and the electrons in the σ-
bond are accepted by the π* orbital of the nitroso group
(Figure 1c). This back-donation process forms an additional
bond between the nitrogen atom and the carbon atom of the
carbonyl group, which stabilizes the zwitterionic structure in
TS1.
Now we revisit the results of Table 1. Dilution of the
reaction inverted the product ratio of nitrone 12a and N-
hydroxyindolinone 13, and under more diluted conditions, the
formation of N-hydroxyindolinone 13 was efficiently sup-
pressed (entries 8 and 9). Considering these results, the
reaction mechanism provided in Scheme 6 should be slightly
modified. Under more diluted, and therefore less basic
conditions, the α-hydroxyketone intermediate tends to exist
as neutral alcohol 18′ (Scheme 7). If the alcohol is further
transformed into the nitrone without deprotonation, then the
previously described results can be explained. Using DFT
calculations, we successfully obtained a neutral structure of
transition state TS2 with an activation energy of +23.5 kcal/
mol. The transition state involved an intramolecular 1,6-
hydride shift from the secondary alcohol moiety to the nitroso
group, or the reaction might be ascribed to dihydrogen
transfer, like a reaction between diimide and olefins.16 On the
contrary, the transition state of the Cannizzaro-like hydride
shift (TS3) was also obtained with an activation energy of
+14.3 kcal/mol. Compared with the activation energy of
formation of N-hydroxyindolinone (TS1, +10.7 kcal/mol), the
preferential formation of N-hydroxyindolinone 13, rather than
nitrone 12, under more basic conditions (entry 8) was
reasonable.17
a
Activation Gibbs energies at 333.15 K (60 °C) are given in kcal/mol.
Interatomic distances are given in angstroms.
In conclusion, we have established conditions for nitrone
formation by reactions of enolates with a nitro group.
Additional experimental results, including isolation of N-
hydroxyindolinone as a byproduct, led to a proposed reaction
mechanism via an α-hydroxyketone. These results suggested
that the nitro group could react with an enolate without
conjugating each other, forming the C−N bond. The resulting
nitrones could be applied to inter- and intramolecular 1,3-
dipolar cycloaddition to give a variety of polycyclic
isoxazolidines.
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c00603.
Experimental details, characterization data, calculation
method, and NMR spectra (PDF)
AUTHOR INFORMATION
■
Corresponding Author
Satoshi Yokoshima − Graduate School of Pharmaceutical
Sciences, Nagoya University, Nagoya 464-8601, Japan;
orcid.org/0000-0003-4036-0062; Email: yokosima@
ps.nagoya-u.ac.jp
Authors
Hiroaki Shimizu − Graduate School of Pharmaceutical
Sciences, Nagoya University, Nagoya 464-8601, Japan
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[2,3-e][1]benzazocine. Tetrahedron 1994, 50, 9769−9774. (c) Bon-
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Soc. 1995, 117, 11017−11018. (d) Solé, D.; García-Rubio, S.;
Kohei Yoshinaga − Graduate School of Pharmaceutical
Sciences, Nagoya University, Nagoya 464-8601, Japan
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c00603
́
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was financially supported by JSPS KAKENHI (grant
number JP17H01523) and by the Platform Project for
Supporting Drug Discovery and Life Science Research (Basis
for Supporting Innovative Drug Discovery and Life Science
Research: BINDS) from the Japan Agency for Medical
Research and Development (AMED) under grant number
JP20am0101099.
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(15) During the preparation of 12h, the formation of 2-
pyridinecarboxaldehyde was observed.
(16) (a) Pasto, D. J.; Chipman, D. M. Theoretical study of the
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2290−2296. (b) McKee, M. L.; Squillacote, M. E.; Stanbury, D. M.
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(17) A reaction of 22 under the conditions of entry 8 in Table 1,
performed in methanol-d4 for 12 h, resulted in the complete
deuteration of the α-positions of ketones 22 and 23. These results
indicated that the conditions of entry 8 were more basic than those of
entry 9.
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Org. Lett. 2021, 23, 2704−2709