Comparison of Substituting Ability of Nitronate versus Enolate for Direct Substitution of a Nitro Group

Article abstract of DOI:10.3390/molecules25092048

α-Nitrocinnamate underwent the conjugate addition of an active methylene compound such as nitroacetate, 1,3-dicarbonyl compound, or α-nitroketone, and the following ring closure afforded functionalized heterocyclic frameworks. The reaction of cinnamate with nitroacetate occurs via nucleophilic substitution of a nitro group by the O-attack of the nitronate, which results in isoxazoline N-oxide. This protocol was applicable to 1,3-dicarbonyl compounds to afford dihydrofuran derivatives, including those derived from direct substitution of a nitro group caused by O-attack of enolate. It was found the reactivity was lowered by an electron-withdrawing group on the carbonyl moiety. When α-nitroketone was employed as a substrate, three kinds of products were possibly formed; of these, only isoxazoline N-oxide was identified. This result indicates that the substituting ability of nitronate is higher than that of enolate for the direct SN2 substitution of a nitro group.

Full text of DOI:10.3390/molecules25092048

molecules
Article
Comparison of Substituting Ability of Nitronate
versus Enolate for Direct Substitution of a
Nitro Group
Yusuke Mukaijo 1, Soichi Yokoyama 1,2,3 and Nagatoshi Nishiwaki 1,2,
*
1
School of Environmental Science and Engineering, Kochi University of Technology, Tosayamada, Kami,
Kochi 782-8502, Japan; 235030n@gs.kochi-tech.ac.jp (Y.M.); yokoyama.soichi@sanken.osaka-u.ac.jp (S.Y.)
Research Center for Molecular Design, Kochi University of Technology, Tosayamada, Kami,
Kochi 782-8502, Japan
The Institute of Scientific and Industrial Research, Osaka University, Mihogaoka, Ibaraki,
Osaka 567-0047, Japan
2
3
*
Correspondence: nishiwaki.nagatoshi@kochi-tech.ac.jp; Tel.: +81-887-57-2517
ꢀꢁꢂꢀꢃꢄꢅꢆꢇ
ꢀꢁꢂꢃꢄꢅꢆ
Academic Editors: Mário J. F. Calvete and Fawaz Aldabbagh
Received: 9 April 2020; Accepted: 23 April 2020; Published: 28 April 2020
Abstract: α-Nitrocinnamate underwent the conjugate addition of an active methylene compound such
as nitroacetate, 1,3-dicarbonyl compound, or -nitroketone, and the following ring closure afforded
α
functionalized heterocyclic frameworks. The reaction of cinnamate with nitroacetate occurs via
nucleophilic substitution of a nitro group by the O-attack of the nitronate, which results in isoxazoline
N-oxide. This protocol was applicable to 1,3-dicarbonyl compounds to afford dihydrofuran derivatives,
including those derived from direct substitution of a nitro group caused by O-attack of enolate.
It was found the reactivity was lowered by an electron-withdrawing group on the carbonyl moiety.
When α-nitroketone was employed as a substrate, three kinds of products were possibly formed; of
these, only isoxazoline N-oxide was identified. This result indicates that the substituting ability of
nitronate is higher than that of enolate for the direct SN2 substitution of a nitro group.
Keywords: conjugate addition; dihydrofuran; 1,3-dicarbonyl compound; enolate; isoxazoline N-oxide;
nitro group; nitroketone; nitronate; nucleophilic substitution
1. Introduction
The nitro group is one of the important functional groups because of its unique chemical properties,
which are useful in many compounds. The strong electron-withdrawing property of the nitro group
reduces the electron density of the adjacent atom or double bond through both inductive and resonance
effects. The increased electrophilicity facilitates nucleophilic addition to a nitroalkene, while the
resulting anionic intermediate is stabilized by the nitro group. The nitro group also serves as a good
leaving group. Nitroalkane undergoes E2 elimination of nitrous acid to afford C–C double bonds
under basic [
in which a nitrite ion is eliminated. The high acidity of an
nitronate, which possesses both nucleophilic [ ] and electrophilic sites to serve as a 1,3-dipole [10,
1
–
4
] or acidic conditions [
5
,
6
]. Direct SN2 substitution is also sometimes observed [
-proton of the nitro group easily generates a
11].
7],
α
8
,9
Moreover, the nitro group is a precursor of amino and carbonyl groups by reduction and Nef-type
reactions [12], respectively. The many properties of the nitro group have facilitated diverse applications.
Recently, the complex/mixed properties of the nitro group have attracted considerable attention
for the synthesis of multi-functionalized/polyfunctionalized compounds. In our previous work,
α
-nitrocinnamate served as a precursor of functionalized enynes via conjugate addition of an acetylide
ion followed by elimination of a nitrous acid [
1]. When
α
-chloro-
α
,β-unsaturated ketone is subjected
Molecules 2020, 25, 2048; doi:10.3390/molecules25092048
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to the reaction with cyano-aci-nitroacetate, intramolecular nucleophilic substitution of the chloro group
by the nitronate ion occurs after Michael addition [13]. Based on these works, this study furthered
this topic by studying the synthesis of functionalized heterocyclic compounds using a combination
of conjugate addition of an active methylene compound and subsequent O-attack of the resulting
nitronate/enolate which undergoes direct substitution of the nitro group. The substituting abilities of
the nitronate/enolate were compared.
2. Results and Discussion
As a highly electron-deficient substrate, methyl α-nitrocinnamate (1a) was employed because of
its easy availability via condensation of benzaldehyde and nitroacetate in the presence of piperidine
hydrochloride with the removal of water as an azeotrope mixture. Indeed, the reaction of 1a with
propylamine quantitatively proceeded at room temperature in acetonitrile to afford product 2a as
a 1:1 mixture of diastereomers, which implies that two stereocenters were newly formed; however,
the product was not an adduct of 1a and propylamine. Based on spectral data of the reaction
mixture, compound 2a was confirmed to be an adduct of 1a with methyl nitroacetate generated in situ.
This reaction is thought to proceed as shown in Scheme 1. After conjugate addition of propylamine
to 1a, C–C bond cleavage forms nitroacetate [14]. Indeed, signals of 1-phenyl-N-propylmethanimine
(3
) were observed in the 1H NMR spectrum of the reaction mixture (see Supplementary Materials).
The generated nitroacetate underwent the conjugate addition to another cinnamate 1a to afford product
2a. However, product 2a could not be isolated by column chromatography because of its instability
on silica gel. On the other hand, when the mixture of 2a and 3 was left at room temperature without
solvent for 7 days, ring closure proceeded to afford isoxazoline N-oxide 4a, in which the nitronate
underwent the direct substitution of the nitro group to form an isoxazoline framework (Scheme 1).
There have been several studies of the formation of isoxazoline N-oxides from
α
-nitro-
(ethoxycarbonylmethyl)dimethylsulfonium salt [16], (ethoxycarbonylmethyl)ammonium salt [17],
(ethoxycarbonylmethyl)pyridinium salt [18], -halomalonate [19], and -iodo aldehyde [20].
-Dimethoxynitroethene is also usable as a nucleophile in this protocol [21]. Among these, only two
methods employ a nitro group as a leaving group [15 21]. In these reactions, the nucleophilicity of the
α
,
β
-unsaturated esters with C–H acids such as secondary nitroalkane
[15],
α
α
β,β
,
nitronate ion is relatively high. To the contrary, nucleophilicity of the nitronate in 2a is considered to
be lower due to the electron-withdrawing ester functionality.
Thus, ethyl
triethylamine. It was confirmed that the successive conjugate-addition/ring-closure reactions efficiently
proceeded in one pot to afford isoxazoline N-oxide 4b 22] (Scheme 2). This result prompted the
study of -nitrocinnamate 1b reactions with other active methylene compounds such as 1,3-dicarbonyl
α-nitrocinnamate (1b) was allowed to react with ethyl nitroacetate in the presence of
[
α
compounds, because the nucleophilicity of the enolate ion is considered to be lower than that of the
nitronate ion.

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Scheme 1. Reaction of
plausible mechanisms.
α-nitrocinnamate 1a with propylamine and the subsequent ring closure, with
Scheme 2. Synthesis of isoxazoline N-oxide 4b.
Although two studies on the reactions of 1b with -keto esters were found in the literature [23,24],
β
they were not conducted under same conditions (one reaction was conducted in the presence of
tetrabutylammonium bromide). In order to compare the reactivity systematically and to generalize
this protocol, the same reaction conditions should be used. Therefore, 1,3-dicarbonyl compounds 5a–f
were subjected to reactions with 1b in the presence of triethylamine at 60 ◦C for 3 h in acetonitrile
(Table 1). Cyclization efficiently proceeded to produce a furan derivative 6a [23] with 92% yield when
ethyl acetoacetate was employed as a substrate (entry 1). The nucleophilicity of the enolate of the
ketone functionality was higher than that of the ester functionality because of the electron-withdrawing
inductive effect of the ethoxy group. Next, the acetyl group of 5a was replaced with a trifluoroacetyl
group. In this case, decreasing the nucleophilicity of the enolate ion was more effective than increasing
the acidity of the methylene group, which produced 5-(trifluoromethyl)-2,3-dihydrofuran 6b with a

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lower yield (entry 2). When benzoylacetate 5c was reacted under the same conditions, the cyclization
occurred without significant effects from the steric hindrance of the phenyl group to furnish the
corresponding dihydrofuran 6c (entry 3). Diketone 5d, acetylacetone, exhibited higher reactivity than
keto esters 5a
also underwent the reaction efficiently to produce bicyclic furan 6e, which was not influence by steric
strain (entry 5) [23 25]. On the other hand, the formation of ester-substituted furan 6f was not detected
–c, and yielded 6d [24] quantitatively (entry 4). Cyclic diketone 5e, 1,3-cyclohexanedione,
,
when diester 5f was subjected to the reaction conditions because of the low nucleophilicity of the
enolate ion (entry 6).
Table 1. Synthesis of functionalized 2,3-dihydrofuran 6.
Entry
R1
R2
5 and 6
Yield/%
1
2
3
4
5
6
Me
CF3
Ph
OEt
OEt
OEt
Me
a
b
c
d
e
f
92
43
62
quant.
quant.
0
Me
–(CH2)3–
OEt
OEt
In the reaction of cinnamate 1b and diketone 5d, the conjugate addition of enolate ion of 5d to
1b afforded adduct intermediate 8d, from which 2,3-dihydrofuran 6d was formed by the substitution
of the nitro group. In other words, 2,3-dihydrofuran 6d was also synthesized if intermediate 8d was
formed [24]. Indeed, when diacetylated styrene
7 was reacted with ethyl nitroacetate in the presence of
triethylamine under the same conditions, a high yield of dihydrofuran 6d was obtained (Scheme 3).
Scheme 3. Synthesis of 2,3-dihydrofuran 6d from either diacetylated styrene 7 or cinnamate 1b.

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Next,
α
-nitroketone
9
was employed as a nucleophile able to produce both an enolate and a
nitronate ion, which facilitated the comparison of the substituting ability of these anions directly
(Scheme 4). In this case, adduct 10 is thought to have formed intermediately, from which three possible
structures 11–13 could be produced. Dihydrofuran 11 was formed by the attack of enolate (Path a),
and isoxazoline N-oxide 12 is formed by the attack of nitronate derived from nitroketone (Path b).
On the other hand, attack of the nitronate derived from nitrocinnamate affords isoxazoline N-oxide 13
(Path c).
Scheme 4. Reaction of cinnamate 1b with nitroketone 9 and three possible products 11–13.
When cinnamate 1b was allowed to react with nitroketone
9 in the presence of triethylamine,
the reaction mixture became somewhat complex, so only one cyclic product was isolated as a major
product. Since a lot of small signals were observed in the 1H NMR spectrum of the reaction mixture,
it is difficult to know whether cyclic products were formed as minor products or not. In the 13C
NMR spectrum of the major product, a signal corresponding to carbonyl carbon was observed at
191 ppm, which indicated that the product had a ketone functionality; thus, the possibility of 11 was
excluded. In the 1H-1H NOESY 2D NMR spectrum, a correlation was observed between the proton at
the 5-position of the isoxazoline ring and the ortho-proton of the benzoyl group, by which the product
was determined to be isoxazoline N-oxide 13.
This result indicated that the nitronate ion substituted a nitro group via Path c. It is considered
that the different reactivity of the two nitro groups was caused by the different electron-withdrawing
ability of the ketone and the ester functionalities. The stronger electron-withdrawing toluoyl group

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increased the electrophilicity of the
α
-carbon and decreased the nucleophilicity of the nitronate ion,
which facilitated the reaction via Path c leading to the predominant formation of 13.
3. Experimental Section
3.1. General
All reagents were purchased from commercial sources and used without further purification.
1H and 13C NMR spectra were recorded on Bruker DPX-400 spectrometer (400 MHz and 100 MHz,
respectively, Billerica, MA, USA) in CDCl3 using TMS as an internal standard. The 13C NMR
assignments were performed via DEPT experiments. A Shimadzu IR spectrometer equipped with an
ATR detector (Kyoto, Japan) was used to record infrared spectra. High-resolution mass spectra were
obtained on an AB SCIEX Triplet TOF 4600 mass spectrometer (Framingham, MA, USA). Melting points
were recorded on a Stanford Research Systems Optimelt automated melting point system (Sunnyvale,
CA, USA) and were uncorrected.
3.2. Synthesis of Isoxazoline N-oxide 4b
To a solution of ethyl
α
-nitrocinnamate 1b (94.6 mg, 0.43 mmol) in acetonitrile (1.3 mL), ethyl
L, 0.43 mmol) were added, and the resultant
nitroacetate (48 L, 0.43 mmol) and triethylamine (60
µ
µ
mixture was stirred at room temperature for 30 min. After removal of the solvent under reduced
pressure, the residual brown oil was dissolved in ethyl acetate (10 mL) and washed with water (10 mL
×
4), and then dried over magnesium sulfate. After removal of the solvent, the residue was purified by
column chromatography on silica gel to afford isoxazoline N-oxide 4b (eluted with hexane/EtOAc =
8/2, 121 mg, 0.41 mmol, 95%) as a yellow solid.
3,5-Bis(ethoxycarbonyl)-4-phenyl-2-isoxazoline 2-oxide (4b) [22]. Yellow solid, yield; 95%, m.p. 75–76 ◦C.
1H NMR (400 MHz, CDCl3)
δ
7.40–7.30 (m, 5H), 4.93 (d, J = 2.8 Hz, 1H), 4.84 (d, J = 2.8 Hz, 1H), 4.35
(dq, J = 10.8, 7.2 Hz, 1H), 4.32 (dq, J = 10.8, 7.2 Hz, 1H), 4.21 (dq, J = 10.8, 7.2 Hz, 1H), 4.17 (dq, J = 10.8,
7.2 Hz, 1H), 1.35 (dd, J = 7.2, 7.2 Hz, 3H), 1.17 (dd, J = 7.2, 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3)
δ
168.2 (C), 158.1 (C), 138.1 (C), 129.3 (CH), 128.7 (CH), 127.0 (CH), 109.0 (C), 78.8 (CH), 62.7 (CH2), 62.0
(CH2), 52.7 (CH), 14.1 (CH3), 13.9 (CH3).
3.3. Typical Procedure for Synthesis of 2,3-Dihydrofuran 6
To a solution of ethyl
α
-nitrocinnamate 1b (71.5 mg, 0.32 mmol) in acetonitrile (1.0 mL), ethyl
L, 0.32 mmol) were added, and the resultant
acetoacetate 5a (41 L, 0.32 mmol) and triethylamine (45
µ
µ
mixture was heated at 60 ◦C for 3 h. After removal of the solvent under reduced pressure, the residual
orange oil was purified by column chromatography on silica gel to afford 2,3-dihydrofuran 6a (eluted
with hexane/EtOAc = 1/1, 88 mg, 0.29 mmol, 92%) as a pale yellow oil. When other 1,3-dicarbonyl
compounds 5 were used, the experiment was conducted in the same way.
1
2,4-Bis(ethoxycarbonyl)-2,3-dihydro-5-methyl-3-phenylfuran (6a) [23]. Pale yellow oil, yield; 92%. H NMR
(400 MHz, CDCl3)
δ 7.34–7.30 (m, 2H), 7.27–7.22 (m, 3H), 4.83 (d, J = 4.8 Hz, 1H), 4.41 (dq, J = 4.8,
1.2 Hz, 1H), 4.30 (dq, J = 10.8, 7.2 Hz, 1H), 4.26 (dq, J = 10.8, 7.2 Hz, 1H), 4.04 (dq, J = 10.8, 7.2 Hz,
1H), 3.98 (dq, J = 10.8, 7.2 Hz, 1H), 2.40 (d, J = 1.2 Hz, 3H), 1.32 (dd, J = 7.2, 7.2 Hz, 3H), 1.07 (dd, J =
7.2, 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3)
δ 170.1 (C), 168.4 (C), 164.9 (C), 142.6 (C), 128.6 (CH),
127.2 (CH), 127.1(CH), 106.4 (C), 85.8 (CH), 61.8 (CH2), 59.6 (CH2), 52.8 (CH), 14.2 (CH3), 14.1 (CH3),
14.1 (CH3); IR (ATR/cm−1) 1755, 1701, 1651, 1207, 1088, 1038; HRMS (ESI/TOF) calcd. for [M + H]+
C17H21O5: 305.1384, found: 305.1384.
1
2,4-Bis(ethoxycarbonyl)-5-trifluoromethyl-2,3-dihydro-3-phenylfuran (6b). Yellow oil, yield; 43%. H NMR
(400 MHz, CDCl3)
J = 11.6, 7.2 Hz, 1H), 4.30 (dq, J = 11.6, 7.2 Hz, 1H), 4.12 (dq, J = 10.8, 7.2 Hz, 1H), 4.05 (dq, J = 10.8,
7.2 Hz, 1H), 1.33 (dd, J = 7.2, 7.2 Hz, 3H), 1.13 (dd, J = 7.2, 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3)
δ 7.4–7.2 (m, 5H), 4.99 (d, J = 4.8 Hz, 1H), 4.62 (dq, J = 4.8, 2.4 Hz, 1H), 4.32 (dq,
δ

Molecules 2020, 25, 2048
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168.5 (C), 161.2 (C), 151.2 (C, q, J = 40.0 Hz), 139.8 (C), 129.1 (CH), 128.1 (CH), 127.2 (CH), 118.0 (C, q,
J = 271.0 Hz), 113.0 (C, q, J = 3.0 Hz), 86.2 (CH), 62.3 (CH2), 61.1 (CH2), 53.8 (CH), 14.1 (CH3), 13.7
(CH3); IR (ATR/cm−1) 1759, 1728, 1200, 1157, 1111; HRMS (ESI/TOF) calcd. for [M + H]+ C17H18F3O5:
359.1101, found: 359.1092.
1
2,4-Bis(ethoxycarbonyl)-2,3-dihydro-1,3-diphenylfuran (6c). Colorless oil, yield; 62%. H NMR (400 MHz,
CDCl3)
δ 7.98–7.95 (m, 2H), 7.48–7.42 (m, 3H), 7.42–7.35 (m, 4H), 7.35–7.28 (m, 1H), 4.96 (d, J = 4.4 Hz,
1H), 4.62 (d, J = 4.4 Hz, 1H), 4.34 (dq, J = 10.8, 7.2 Hz, 1H), 4.31 (dq, J = 10.8, 7.2 Hz, 1H), 4.01 (dq,
J = 10.8, 7.2 Hz, 1H), 3.98 (dq, J = 10.8, 7.2 Hz, 1H), 1.36 (dd, J = 7.2, 7.2 Hz, 3H), 1.03 (dd, J = 7.2,
7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3)
δ 170.2 (C), 165.4 (C), 164.1 (C), 142.5 (C), 130.1 (CH), 129.8
(CH), 129.2 (C), 128.8 (CH), 127.7 (CH), 127.4 (CH), 127.2 (CH), 106.7 (C), 85.0 (CH), 61.8 (CH2), 59.9
(CH2), 54.1 (CH), 14.2 (CH3), 13.9 (CH3); IR (ATR/cm−1) 1751, 1697, 1628, 1203, 1076, 752, 694; HRMS
(ESI/TOF) calcd. for [M + H]+ C22H23O5: 367.1540, found: 367.1540.
4-Ethanoyl-2-ethoxycarbonyl-2,3-dihydro-5-methyl-3-phenylfuran (6d) [24]. Yellow solid, yield; quant., m.p.
63–64 ◦C. 1H NMR (400 MHz, CDCl3)
δ
7.37–7.33 (m, 2H), 7.30–7.23 (m, 3H), 4.72 (d, J = 4.8 Hz, 1H),
4.49 (dq, J = 4.8, 1.2 Hz, 1H), 4.31 (dq, J = 10.8, 7.2 Hz, 1H), 4.27 (dq, J = 10.8, 7.2 Hz, 1H), 2.44 (d, J =
1.2 Hz, 3H), 1.95 (s, 3H), 1.34 (dd, J = 7.2, 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3)
194.3 (C), 170.0
δ
(C), 168.6 (C), 142.2 (C), 129.1 (CH), 127.6 (CH), 127.2 (CH), 115.1 (C), 86.0 (CH), 61.9 (CH2), 53.3 (CH),
29.6 (CH3), 14.9 (CH3), 14.2 (CH3); IR (ATR/cm−1) 1755, 1674, 1624, 1604, 1196, 1038; HRMS (ESI/TOF)
calcd. for [M + H]+ C16H18O4Na: 297.1097, found: 297.1099.
1
5,6-Cyclohexa-2-ethoxycarbonyl-2,3-dihydro-3-phenylfuran-4-one (6e) [25]. Yellow oil, yield; quant. H
NMR (400 MHz, CDCl3)
4.8 Hz, 1H), 4.32 (dq, J = 10.8, 7.2 Hz, 1H), 4.27 (dq, J = 10.8, 7.2 Hz, 1H), 2.68–2.65 (m, 2H), 2.44–2.31 (m,
2H), 2.19–2.10 (m, 2H), 1.33 (dd, J = 7.2, 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3)
194.3 (C), 177.4 (C),
δ 7.34–7.31 (m, 2H), 7.27–7.21 (m, 3H), 4.96 (d, J = 4.8 Hz, 1H), 4.46 (br d, J =
δ
169.5 (C), 141.1 (C), 128.9 (CH), 127.4 (CH), 127.0 (CH), 115.8 (C), 88.0 (CH), 62.0 (CH2), 49.8 (CH), 36.8
(CH2), 23.9 (CH2), 21.7 (CH2), 14.2 (CH3); IR (ATR/cm−1) 1751, 1639, 1396, 1219, 748; HRMS (ESI/TOF)
calcd. for [M + H]+ C17H19O4: 287.1278, found: 287.1278.
3-Ethoxycarbonyl-4,5-dihydro-5-(4-methylbenzoyl)-4-phenylisoxazoline 2-oxide (13). Yellow oil, yield; 64%.
1H NMR (400 MHz, CDCl3)
δ
7.81 (d, J = 8.0 Hz, 2H), 7.42–7.36 (m, 5H), 7.29 (d, J = 8.0 Hz, 2H), 5.66 (d,
J = 3.6 Hz, 1H), 5.12 (d, J = 3.6 Hz, 1H), 4.19 (dq, J = 10.8, 7.2 Hz, 1H), 4.14 (dq, J = 10.8, 7.2 Hz, 1H),
2.43 (s, 3H), 1.13 (dd, J = 7.2, 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3)
191.3 (C), 158.4 (C), 146.0 (C),
δ
138.6 (C), 130.9 (C), 129.9 (CH), 129.5 (CH), 129.5 (CH), 128.8 (CH), 127.6 (CH), 109.8 (C), 81.7 (CH),
62.0 (CH2), 51.8 (CH), 22.0 (CH3), 14.0 (CH3); IR (KBr/cm−1) 1736, 1697, 1628, 1606, 1228, 740; HRMS
(ESI/TOF) calcd. for [M + H]+ C20H20NO5: 354.1336 found: 354.1337.
4. Conclusions
2,3-Dihydrofurans and isoxazoline N-oxides were synthesized from
methylene compounds by conjugate addition and the subsequent O-attack. Via a series of reactions using
several substrates, the nitro group increased the electrophilicity of the -carbon and served as a good
α-nitrocinnamate 1 and active
α
leaving group. The nitro group also served as a good nucleophile when it was converted to nitronate ion,
which is more reactive than the enolate ion of ketone or ester functionalities. These results will be useful
information for researchers studying synthetic chemistry using the multi-functionalities of a nitro group.
Supplementary Materials: The following are available online. 1H and 13C NMR spectra of 2a, 4, 6 and 13.
Author Contributions: Y.M. did experiments and wrote a draft; S.Y. and N.N. analyzed data and discussed
with Y.M.; all authors contributed to the revision. All authors have read and agreed to the published version of
the manuscript.
Funding: This research received no external funding.
Conflicts of Interest: The authors declare no conflict of interest.

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References
1.
2.
3.
4.
5.
Asahara, H.; Sofue, A.; Kuroda, Y.; Nishiwaki, N. Alkynylation and cyanation of alkenes using diverse
properties of a nitro group. J. Org. Chem. 2018, 83, 13691–13699. [CrossRef]
Nishiwaki, N. Chemistry of nitroquinolones and synthetic application to unnatural 1-methyl-2-quinolone
derivatives. Molecules 2010, 15, 5174–5195. [CrossRef]
Hao, F.; Nishiwaki, N. Recent progress in nitro-promoted direct functionalization of pyridones and quinolones.
Molecules 2020, 25, 673. [CrossRef]
Chiurchi
starting from
ù
, E.; Gabrielli, S.; Ballini, R.; Palmieri, A. A new valuable synthesis of polyfunctionalized furans
-nitroenones and active methylene compounds. Molecules 2019, 24, 4575. [CrossRef] [PubMed]
β
Palmieri, A.; Gabrielli, S.; Ballini, R. Efficient two-step sequence for the synthesis of 2,5-disubstituted
furan derivatives from functionalized nitroalkanes: successive amberlyst A21- and amberlyst 15-catalyzed
processes. Chem. Commun. 2010, 46, 6165–6167. [CrossRef] [PubMed]
6.
7.
Palmieri, A.; Gabrielli, S.; Parlapiano, M.; Ballini, R. One-pot synthesis of alkyl pyrrole-2-carboxylates starting
from β-nitroacrylates and primary amines. RSC Adv. 2015, 5, 4210–4213. [CrossRef]
Mo, Y.; Liu, S.; Liu, Y.; Ye, L.; Shi, Z.; Zhao, Z.; Li, X. Highly stereoselective synthesis of 2,3-dihydrofurans via
a cascade michael addition-alkylation process: A nitro group as the leaving group. Chem. Commun. 2019, 55,
6285–6288. [CrossRef]
8.
9.
Noble, A.; Anderson, J.C. Nitro-mannich reaction. Chem. Rev. 2013, 113, 2887–2939. [CrossRef]
Sukhorukov, A.Y. C-H reactivity of the a-position in nitrones and nitronates. Adv. Synth. Catal. 2020, 362,
724–754. [CrossRef]
10. Baiazitov, R.; Denmark, S.E. Tandem [4 + 2]/[3 + 2] cycloadditions. In Methods and Applications of Cycloaddition
Reactions in Organic Syntheses; Nishiwaki, N., Ed.; John Wiley & Sons: Hoboken, NJ, USA, 2014; pp. 471–550.
11. Nishiwaki, N.; Kumegawa, Y.; Iwai, K.; Yokoyama, S. Development of safely handleable synthetic equivalent
of cyanonitrile oxide by 1,3-dipolar cycloaddition of nitroacetonitrile. Chem. Commun. 2019, 55, 7903–7905.
[CrossRef]
12. Ballini, R.; Petrini, M. The nitro to carbonyl conversion (nef reaction): New perspectives for a classical
transformation. Adv. Synth. Catal. 2015, 357, 2371–2402. [CrossRef]
13. Iwai, K.; Asahara, H.; Nishiwaki, N. Synthesis of functionalized 3-cyanoisoxazoles using a dianionic reagent.
J. Org. Chem. 2017, 82, 5409–5415. [CrossRef] [PubMed]
14. Kallitsakis, M.G.; Tancini, P.D.; Dixit, M.; Mpourmpakis, G.; Lykakis, I.N. Mechanistic studies on the Michael
addition of amines and hydrazines to nitrostyrenes: Nitroalkane elimination via a retro-aza-henry-type
process. J. Org. Chem. 2018, 83, 1176–1184. [CrossRef] [PubMed]
15. Melot, J.M.; Texier-Boullet, F.; Foucaud, A. Alumina supported potassium fluoride promoted reaction of
nitroalkanes with electrophilic alkenes. synthesis of 4,5-dihydrofurans and isoxazoline n-oxides. Tetrahedron
1988, 44, 2215–2224. [CrossRef]
16. Zhu, C.-Y.; Sun, X.-L.; Deng, X.-M.; Zheng, J.-C.; Tang, Y. Synthesis of isoxazoline N-oxides and its application
in the formal synthesis of dehydroclausenamide. Tetrahedron 2008, 64, 5583–5589. [CrossRef]
17. Zhu, C.-Y.; Deng, X.-M.; Sun, X.-L.; Zheng, J.-C.; Tang, Y. Highly enantioselective synthesis of isoxazoline
N-oxides. Chem. Commun. 2008, 738–740. [CrossRef]
18. Chernysheva, N.B.; Maksimenko, A.S.; Andreyanov, F.A.; Kislyi, V.P.; Strelenko, Y.A.; Khrustalev, V.N.;
Victor, V. Synthesis of 3,4-diaryl-5-carboxy-4,5-dihydroisoxazole 2-oxides as valuable synthons for anticancer
molecules. Tetrahedron 2017, 73, 6728–6735. [CrossRef]
19. Le Menn, J.C.; Sarrazin, J.; Tallec, A. Formation of isoxazoline N-oxides and dihydrofurans by
cyclocondensation of bromo- or chloromalonate carbanion with michael acceptors. Bull. Soc. Chim. Fr. 1991
,
562–565.
20. Shi, Z.; Tan, B.; Leong, W.; Wen, Y.; Zeng, X.; Lu, M.; Zhong, G. Catalytic asymmetric formal [4 + 1] annulation
leading to optically active cis-isoxazoline N-oxides. Org. Lett. 2010, 12, 5402–5405. [CrossRef]
21. Chen, X.; Peng, Y.; Yu, W.; Zhang, X.; Shao, X.; Xu, X.; Li, Z. Condition-based selective synthesis of
3,4,5-trisubstituted isoxazoline N-oxides, 4,5-dihydroisoxazoles and isoxazoles. ChemistrySelect 2018, 3,
6344–6348. [CrossRef]
22. Rouf, A.; Sahin, E.; Tanyeli, C. Divergent synthesis of polysubstituted isoxazoles, isoxazoline N-oxides,
and dihydroisoxazoles by a one-pot cascade reaction. Tetrahedron 2017, 73, 331–337. [CrossRef]

Molecules 2020, 25, 2048
9 of 9
23. Zhang, Y.-R.; Luo, F.; Huang, X.-J.; Xie, J.-W. Water-compatible cascade reaction: An efficient route to
substituted 2,3-dihydrofurans. Chem. Lett. 2012, 41, 777–779. [CrossRef]
24. Chuang, C.-P.; Chen, K.-P.; Hsu, Y.-L.; Tsai, A.-I.; Liu, S.-T.
α-nitro carbonyl compounds in the synthesis of
2,3-dihydrofurans. Tetrahedron 2008, 64, 7511–7516. [CrossRef]
25. Berestovitskaya, V.M.; Baichurin, R.I.; Baichuria, L.V.; Fel’gendler, A.V.; Aboskalova, N.I. Geminally activated
β-nitrostyrenes in reactions with cyclic β-diketones. Russ. J. Gen. Chem. 2013, 83, 1755–1763. [CrossRef]
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