An anomalous hydration/dehydration sequence for the mild generation of a nitrile oxide

Article abstract of DOI:10.1039/c0ob01005g

A nitrile oxide containing a carbamoyl group is readily generated upon the treatment of 2-methyl-4-nitro-3-isoxazolin-5(2H)-one with water under mild reaction conditions, even in the absence of special reagents. The obtained nitrile oxide undergoes cycloa

Full text of DOI:10.1039/c0ob01005g

View Article Online / Journal Homepage / Table of Contents for this issue
Organic &
Biomolecular
Chemistry
Dynamic Article Links
Cite this: Org. Biomol. Chem., 2011, 9, 2832
www.rsc.org/obc
PAPER
An anomalous hydration/dehydration sequence for the mild generation of a
nitrile oxide†
Nagatoshi Nishiwaki,*a Kazuya Kobiro,a Hideyuki Kiyoto,a Shotaro Hirao,a Jun Sawayama,a Kazuhiko Saigo,a
Yoshikazu Okajima,b Toshiharu Uehara,b Asaka Makib and Masahiro Arigab
Received 10th November 2010, Accepted 12th January 2011
DOI: 10.1039/c0ob01005g
A nitrile oxide containing a carbamoyl group is readily generated upon the treatment of
2-methyl-4-nitro-3-isoxazolin-5(2H)-one with water under mild reaction conditions, even in the absence
of special reagents. The obtained nitrile oxide undergoes cycloaddition with dipolarophiles, alkynes and
alkenes, to afford the corresponding isoxazol(in)es, which are useful intermediates in the synthesis of
polyfunctionalized compounds. A plausible mechanism underlying the formation of the nitrile oxide is
proposed, which involves an anomalous hydration/dehydration sequence. DFT calculations were also
performed to support this mechanism.
Introduction
1,3-Dipolar cycloaddition plays an important role in synthetic
chemistry because it affords five-membered heterocyclic rings in a
single step. Moreover, the cycloadducts formed in this reaction
and the ring-opened products obtained from the adducts are
precursors of a variety of versatile functional materials.1 With the
growing demand for environmentally-friendly synthesis protocols,
there has been an increased focus on 1,3-dipolar cycloaddition
reactions in aqueous media.2 Nitrile oxide, one of the most
popular classes of 1,3-dipoles, affords isoxazoles, 2-isoxazolines,
and 1,2,4-oxadiazoles upon treatment with alkynes, alkenes, and
nitriles, respectively.1–4 While there are numerous reports on nitrile
oxides, most of them are related to aryl- or alkyl-substituted
nitrile oxides. Nitrile oxides having a suitable functional group
are considered useful for the synthesis of functional materials;
however, such substituted nitrile oxides are not very common in
organic synthesis, probably because they are highly reactive and
their precursors are not readily available.
Fig. 1 Nitrile oxides having a functional group.
tion, tolylene diisocyanate (modified Mukaiyama method),6 man-
ganese(III) acetate,7 acid chloride,8 or trifluoroborane etherate9 is
employed as the generating agent. In addition, nitromalonate10
and nitroacetoacetate11 are known to be precursors of 1; however,
these compounds have certain disadvantages: severe reaction
conditions must be employed when using nitromalonate, and
nitroacetoacetate is highly unstable. Although De Sarlo and
Machetti demonstrated an excellent protocol for the preparation
of functionalized isoxazol(in)es from nitroalkanes, active species
were not functionalized nitrile oxides but activated nitronates.12
Nitrile oxides bearing an amide function have not been
widely utilized in organic syntheses, except in a few intrigu-
ing cases. Paul and Tchelitcheff were the first to isolate the
cycloadduct of N-phenylcarbamoylnitrile oxide 2a (Fig. 1) as
a by-product in a reaction between nitromethane, phenyl iso-
cyanate, and triethylamine.13 Huisgen and Christl showed that
N-phenylnitroacetamide is the precursor of 2a in the above
mentioned reaction.14 Joule et al. also generated a carbamoyl-
nitrile oxide by treating nitroacetamide with thionyl chloride.8a
Among the various functionalized nitrile oxides reported, the
ethoxycarbonyl derivative 1 (Fig. 1) is most commonly used in
organic synthesis. Nitrile oxide 1 is generated by the dehydrochlo-
rination of hydroximoyl chlorides, which is synthesized from ethyl
glyoxylate or glycine ethyl ester.5 A method for the dehydration
of ethyl nitroacetate to 1 has also been established; in this reac-
aSchool of Environmental Science and Engineering, Kochi Univer-
sity of Technology, Tosayamada Kami, Kochi, 782-8502, Japan.
E-mail: nishiwaki.nagatoshi@kochi-tech.ac.jp; Fax: +81 887 57 2520;
Tel: +81 887 57 2517
bDepartment of Chemistry, Osaka Kyoiku University, Asahigaoka, Kashi-
wara, Osaka, 582-8582, Japan
† Electronic Supplementary Information (ESI) available: 1H and 13C
NMR spectra of products 3, 8, 11, and 18, preparative method for
nitroisoxazolone 5a, cartesian coordinates of all reported structures and
the energies are also available. See DOI: 10.1039/c0ob01005g
2832 | Org. Biomol. Chem., 2011, 9, 2832–2839
This journal is
The Royal Society of Chemistry 2011
©

View Article Online
Shimizu,15 Webb,6b and Schults16 reported a different method
involving the use of a-nitromalonic acid amide ester 3a as a
precursor for generating 2a; however, in this method, severe
reaction conditions were required (Scheme 1). Moreover, although
dehydrochlorination of carbamoylformhydroxymoyl chloride by
triethylamine is also known to be another route to 2a, multi-step
reactions are necessary for preparation of the starting chloride.17
Recently, nitrile oxides having an N-modified carbamoyl group
such as Weinreb amide 2b18 and chiral amide 2c19 have been synthe-
sized (Fig. 1). Although these nitrile oxides possess inherently high
synthetic values, the corresponding precursors are troublesome to
prepare. Therefore, development of a facile method to generate
2 under mild conditions is necessary. In the present paper, we
demonstrate a new route to carbamoylnitrile oxide 2d from 2-
methyl-4-nitro-3-isoxazolin-5(2H)-one (5a) which can be easily
prepared as shown in Scheme 2.20
Scheme 3 Chemical transformation of nitroisoxazolone 5a.
remain intact, but bubbles were formed in the reaction mixture
after activated carbon was added. From this mixture, bis(N-
methylcarbamoyl)-1,2,5-oxadiazole-2-oxide (furoxan) (6) could
be isolated in 40% yield (based on 5a), indicating the in situ
generation of carbamoylnitrile oxide (2d, R1 = Me, R2 = H) from
nitroisoxazolone 5a and the concurrent elimination of carbon
dioxide. However, the role of activated carbon in this reaction
has not yet been clarified. Cycloaddition of 2d proceeded to afford
3-(N-methylcarbamoyl)-5-phenylisoxazole (8a) in 66% yield when
activated carbon was added to a solution of 5a and ethynylbenzene
7a under the same conditions mentioned above (heating at 100 ◦C
in DMF).23 A small amount of furoxan 6 was also isolated from
the aqueous solution used for the workup of the other reaction
involving nitroisoxazolone 5a. In this case, nitrile oxide 2d was
formed even when activated carbon was not employed, indicating
that this nitrile oxide was generated by another generating agent,
presumably water. This hypothesis prompted us to reinvestigate
the generation of carbamoylnitrile oxide 2d in aqueous media.
An aqueous solution of nitroisoxazolone 5a was stirred at
30 ◦C for 1 day without adding any other reagent, and then,
water was removed under reduced pressure. The residue was
purified by silica gel column chromatography to afford furoxan
6 in 80% yield (based on 5a), together with a trace amount of
N-methylnitroacetamide 9.24 The successful isolation of furoxan
6 indicated that water triggered the generation of nitrile oxide
2d under the above mentioned reaction conditions, as expected.
Cycloaddition of 2d to 7a proceeded under the same conditions
mentioned above to afford isoxazole 8a in 22% yield (Table 1,
run 1). Since the low efficiency of the cycloaddition reaction was
attributed to the low solubility of 7a in water, an acetonitrile–water
(3/1, v/v) mixture was used to improve the solubility of both
isoxazolone 5a and the dipolarophile 7a. Although the amount
of water could be diminished to the ratio (6/1, v/v), almost
all nitroisoxazolone 5a was recovered in the case of (9/1, v/v)
Scheme 1 Conversion of malonic acid amide ester 3a to nitrile oxide 2a.
Scheme 2 Preparation of nitroisoxazolone 5.
Results and Discussion
Nitroisoxazolone 5a readily reacted with amines to afford a-
amino-b-nitroenamines (nitroketene aminals) and amidoximes21
and underwent ring transformation to afford polyfunctionalized
pyrroles upon treatment with sodium enolates of 1,3-dicarbonyl
compounds (Scheme 3).22 Upon heating in DMF at 100 ◦C
in the absence of a nucleophile, isoxazolone 5a was found to
This journal is
The Royal Society of Chemistry 2011
Org. Biomol. Chem., 2011, 9, 2832–2839 | 2833
©

View Article Online
Table 1 Study on reaction conditions
Table 2 Cycloaddition of nitrile oxide 2d generated from 5a and dipo-
larophiles 7 and 10
run
Solv.
7a/equiv.
Temp./◦C
Yield/%
1
2
H2O
MeCN–H2O
(3/1)
1.2
1.2
30
30
22
55
3
4
5
6
7
MeCN–H2O
(6/1)
MeCN–H2O
(9/1)
MeCN–H2O
(3/1)
MeCN–H2O
(3/1)
1.2
1.2
1.2
5.0
5.0
30
30
60
30
30
47
trace
55
72
THF–H2O
(3/1)
65
run Substrate R1
R2
H
R3
R4
Product Yield/%
1
2
3
4
5
6
7
8
9
7a
Ph
8a
72
84
58
74
85
73
63
quant.
76
0
7b
CH2OH H
CH2Br
COOEt COOEt
8b
7c
7d
10a
10b
10c
10d
10e
H
8c
8d
ratio (runs 2–4). Under these conditions, considerable amounts
of furoxan 6 were formed as the by-product; a similar result
was obtained even at higher temperature (run 5). The above
disadvantage was overcome by using excess dipolarophile, and
the yield of 8a in this case was improved up to 72% (run 6). When
THF was used as a co-solvent in the present reaction, the yield
of 8a was comparable to that mentioned in the previous sentence
(run 7); however, acetonitrile was preferred because of the high
solubility of 5a in this solvent.
Ph
Pr
-(CH2)3-
CH2OH
CH2OEt
CH2NH2
CH2NHAc H
OEt
-(CH2)2O-
COOEt
H
H
11a
11b
11c
11d
11e
11f
11g
11h
11i
11j
H
H
H
10 10f
11 10g
12 10h
13 10i
14 10j
15 10k
16 10l
23
78
78
92
67a
63
H
H
Other dipolarophiles 7b–d and 10a–l were subjected to cycload-
dition under the optimized conditions used for ethynylbenzene
7a (Table 2, run 1). Propargyl derivatives 7b and 7c underwent
this cycloaddition reaction to afford cycloadducts 8b and 8c,
respectively (runs 2 and 3). A trifunctionalized isoxazole 8d was
prepared in a similar manner from electron-deficient alkyne 7d
(run 4). Nitrile oxide 2d also underwent the aforementioned
cycloaddition with olefinic hydrocarbons 10a–c to afford the
corresponding 2-isoxazolines (4,5-dihydroisoxazoles) 11a–c (runs
5–7). Allylalcohol 10dhadhigher reactivitythandidhydrocarbons
and allyl ethyl ether 10e; the hydroxy group in 10d was thought
to participate in the generation of nitrile oxide 2d (runs 8 and 9).
On the other hand, allylamine 10f afforded a complex mixture, in
which desired cycloadduct 11f could not be detected, presumably
because of competitive reactions triggered by the nucleophilic
amino group, as shown in Scheme 3 (run 10). This problem was
partially solved by protecting the amino group with an acetyl
group, in which case 11g was obtained, albeit in low yield (run 11).
The present reaction was applicable to electron-rich alkenes such
as vinyl ethers 10h and 10i, as well as to electron-deficient alkenes
such as acrylate 10j, maleate 10k, and enone 10l: alkenes 10h–l
gave the corresponding cycloadducts 11h–l in good to excellent
yields (runs 12–16). It is noteworthy that the cycloaddition of 2d
with monosubstituted alkenes proceeded regioselectively to afford
5-substituted 2-isoxazolines 11 independent of the electronic
property of the dipolarophiles.
COOMe COOMe 11k
COMe 11l
H
a A mixture of cis- and trans-isomers was formed in a 93/7 ratio.
anionic isoxazolone 4a is deprotonated by pyrrolidine, the ring
proton of N-methylisoxazolone 5a should be sufficiently acidic
for easy deprotonation by water. 2,3-Dimethylnitroisoxazolone
5b,25 which has no ring protons, remains intact under the same
conditions to be recovered, although the steric effect of the
additional methyl group in this compound must be taken into
consideration. On the basis of these observations, we propose
a plausible mechanism for the generation of nitrile oxide 2d, as
shown in Scheme 5. According to this mechanism, the first step in
the formation of 2d is deprotonation at the 3-position by water.
The successive ring-opening reaction furnishes the ketenimine in-
termediate 13. As reviewed by Prager and Williams,26 a number of
base-induced ring-opening reactions of 3-isoxazolin-5-ones have
been studied; in these reactions, the N–O bond fission initiated by
deprotonation at the 3-position affords malonic acid derivatives
via the formation of ketenimine and b-lactone intermediates.27
In our reaction, the cummulene carbon of ketenimine 13 is
attacked by water to afford a-hydroxy-b-nitroenamine 14 (route
a), which in turn undergoes a tautomeric rearrangement to form
nitroacetamide 9 by tautomerism. Another reaction path (route
b), which involves the intramolecular attack of carboxylate on the
cummulene carbon to give b-lactone 15, can also be considered.
Compound 15 is expected to be highly reactive and hence reacts
readily with water. When the enamine moiety is attacked by water
(route c), the resulting intermediate is 14, which tautomerizes to
We have previously demonstrated that the anionic nitroisoxa-
zolone 4a undergoes ring opening to form dianionic cyano-aci-
nitroacetate 12 by cation exchange and subsequent deprotonation
at the 3-position of the isoxazolone ring (Scheme 4).20c Since even
2834 | Org. Biomol. Chem., 2011, 9, 2832–2839
This journal is
The Royal Society of Chemistry 2011
©

View Article Online
polarization and diffuse functions (6-31+G**) is used. Model
compound 17¢ has ten conformers, each with two or three
intramolecular hydrogen bonds. Among them, one conformer 17¢
nicely leads to 2d¢ via transition state 19; the activation energy in
this case is 11.6 kcal mol-1, as shown in Scheme 7 and Fig. 2. The
˚
interatomic distance (2.68 A) between N1 of the carbamoyl group
and O5 of the carboxyl group in 19 clearly indicates the existence of
strong intramolecular hydrogen bonding in this compound, even
in the transition state; this hydrogen bonding is responsible for the
planar geometry of the transition state. The generation of 2d from
17 under the quite mild conditions can be ascribed to the planarity
of the transition state, which favors concerted decarboxylation and
dehydration.
Scheme 4 Ring opening reaction of anionic isoxazolone 4a.
nitroacetamide 9. On the other hand, when water attacks the
carbonyl group of 15 (route d), nitromalonic acid monoamide 17 is
formed which readily undergoes dehydration and decarboxylation
in a concerted manner to afford nitrile oxide 2d. Another
possibility is that 15 may undergo prototropic rearrangement to
form the less-strained intermediate 16 (route e), in which the two
electrophilic carbons are attacked bywater to give the nitromalonic
acid derivative 17 (route f or g). In the present mechanism, nitro-
enamine 14 and nitromalonic acid derivative 17 are considered
the key intermediates. This consideration is supported by the
experimental fact that methanolysis of isoxazolone 5a affords
a mixture of methoxynitroenamine 18 and a small amount of
nitromalonic acid amide ester 3d, which are corresponding to
hydroxy derivatives 14 and 17, respectively (Scheme 6).
Nitroacetates can be used as the precursors of nitrile oxide 1,
which has an ester function; however, dehydrating agents and
severe conditions need to be employed for this conversion.6–9
Indeed, nitroacetamide 9, the tautomer of hydroxynitroenamine
14, is not converted to nitrile oxide 2d upon treatment with an
acetonitrile–water (3/1, v/v) mixture alone. Hence, the precursor
of 2d is thought to be nitromalonic acid derivative 17 and
not nitroenamine 14. As shown in Scheme 1, the nitromalonic
acid amide ester 3a serves as the precursor of nitrile oxide
2a under severe reaction conditions.10 In contrast, our method
efficiently generates nitrile oxide 2d at room temperature even
when no special reagent is employed; the carbamoyl group of 16
is thought to play an important role in dehydration as well as
decarboxylation.
Fig. 2 Calculated geometry of transition state 19.
Conclusions
Nitroisoxazolone 5a serves as the precursor of nitrile oxide
2d, which has a carbamoyl group and undergoes cycloaddition
with various dipolarophiles at 30 ◦C to afford functionalized
isoxazol(in)es 8 and 11 in good yields. In the present method, only
water is required for the generation of 2d, while other methods
for synthesizing nitrile oxides require the use of special generators
such as bases, oxidants, and dehydrating agents. Moreover, the
present reaction can be conducted in air with simple experimental
manipulations. These advantages make the proposed method a
very useful tool in organic syntheses.
A plausible mechanism for this reaction is also proposed.
According to this mechanism, nitromalonic acid monoamide
17 is the precursor of nitrile oxide 2d; this assumption is well
supported by the results of DFT calculations performed using
B3LYP/6-31+G**. The calculation result also indicates that the
carbamoyl group takes part in the concerted decarboxylation and
dehydration assisted by intramolecular hydrogen bonding. This
concerted reaction enables the easy formation of nitrile oxide 2d
even under mild conditions.
Theoretical calculations were performed to investigate the
plausible reaction pathway by using a simplified model com-
pound nitromalonic acid monoamide 17¢, which is converted to
carbamoylnitrile oxide 2d¢. For this purpose, the DFT method
based on Becke¢s nonlocal three-parameter hybrid functional is
employed in combination with the Lee, Yang, and Parr correlation
functional (B3LYP). A split valence double-z basis set with extra
Experimental
General
The melting points were determined on a Yanaco micro-melting-
points apparatus, and were uncorrected. All the reagents and
This journal is
The Royal Society of Chemistry 2011
Org. Biomol. Chem., 2011, 9, 2832–2839 | 2835
©

View Article Online
Scheme 5 A plausible mechanism for generation of nitrile oxide 2d.
solvents were commercially available and used as received. The
1H NMR spectra were measured on a Bruker DPX-400 or Varian
UNITY INOVA 400 at 400 MHz with TMS as an internal
standard. The 13C NMR spectra were measured on a Bruker DPX-
400 or Varian UNITY INOVA 400 at 100 MHz, and assignments
of 13C NMR spectra were performed by DEPT experiments. The
IR spectra were recorded on a Horiba FT-200 IR spectrometer
and a JASCO FT/IR-4200 Spectrophotometer. The mass spectra
were recorded on a JEOL JMS-AX505HA. The high resolution
mass spectra were measured on a JEOL JMS-700 MStation. The
elemental microanalyses were performed using a Yanaco MT-3
CHN corder.
Scheme 6 Methanolysis of nitroisoxazolone 5a.
ethyl nitroacetate by three steps with simple experimental
manipulations; 1) condensation of nitroacetate with orthoformate,
2) condensation with hydroxylamine, and 3) N-methylation with
dimethyl sulfate (Details are given in the ESI†).20
3,4-Bis(N-methylcarbamoyl)-1,2,5-oxadiazole
(Furoxan) (6)8a,23
A solution of nitroisoxazolone 5a (72 mg,
0.50 mmol) in water (5.0 mL) was stirred at 30 ◦C for 1 day. When
2-Oxide
2-Methyl-4-nitro-3-isoxazolin-5(2H)-one
(5a). Nitroisox-
.
azolone 5a was easily prepared from commercially available
2836 | Org. Biomol. Chem., 2011, 9, 2832–2839
This journal is The Royal Society of Chemistry 2011
©

View Article Online
68 (25), 58 (100). HRMS Calcd for C6H8N2O3: 156.0535. Found:
156.0535.
5-Bromomethyl-3-(N-methylcarbamoyl)isoxazole (8c). Eluted
with hexane–AcOEt (80/20). Colorless plates. Mp 133–134 ◦C. IR
1
(KBr) 3343, 1671 cm-1; H NMR (400 MHz, CDCl3) d 3.00 (d,
J = 4.8 Hz, 3H), 4.48 (s, 2H), 6.76 (s, 1H), 6.7–6.9 (br, 1H); 13C
NMR (100 MHz, CDCl3) d 18.0 (CH2), 26.1 (CH3), 103.5 (CH),
158.8 (C), 158.9 (C), 169.0 (C); MS (EI) 220 (M+, 1), 125 (17), 68
(14), 58 (100). Anal. Calcd for C6H7N2O2Br: C, 32.90; H, 3.22; N,
12.79%. Found: C, 32.83; H, 3.22; N, 12.82%.
4,5-Bis(ethoxycarbonyl)-3-(N-methylcarbamoyl)isoxazole (8d).
Eluted with hexane–AcOEt (80/20). Colorless plates. Mp 116–
◦
1
118 C. IR (neat) 3300, 1732, 1670 cm-1; H NMR (400 MHz,
CDCl3) d 1.400 (t, J = 7.2 Hz, 3H), 1.404 (t, J = 7.2 Hz, 3H),
3.02 (d, J = 5.2 Hz, 3H), 4.45 (q, J = 7.2 Hz, 2H), 4.46 (q, J =
7.2 Hz, 2H), 6.8–6.9 (br, 1H); 13C NMR (100 MHz, CDCl3) d 13.82
(CH3), 13.84 (CH3), 26.2 (CH3), 62.7 (CH2), 63.0 (CH2), 117.3 (C),
155.2 (C), 156.2 (C), 157.3 (C), 158.7 (C), 160.3 (C); MS (EI) 225
(2), 197 (6), 140 (9), 112 (11), 68 (18), 58 (100). Anal. Calcd for
C11H14N2O6: C, 48.89; H, 5.22; N, 10.37%. Found: C, 48.87; H,
5.24; N, 10.41%.
Scheme 7 Relative energies (kcal mol-1) for the formation of 2d¢ from 17¢
via transition state 19 with simultaneous decarboxylation and dehydration.
the solvent was removed under reduced pressure, a colorless
crystalline product was obtained which contained furoxan.
Further purification was performed by recrystallization from
benzene to give 6 (40 mg, 0.20◦mmol, yield 80% based on 5a).
◦
Mp 168–169 C (lit.8a 163–165 C). IR (KBr) 3323, 1695, 1653,
1460 cm-1; H NMR (400 MHz, CDCl3) d 3.05 (d, J = 4.8 Hz,
1
4,5-Dihydro-3-(N-methylcarbamoyl)-5-phenylisoxazole (11a)12.
3H), 3.06 (d, J = 4.8 Hz, 3H), 8.5–8.7 (br, 1H), 9.6–9.8 (br, 1H);
1H NMR (400 MHz, DMSO-d6) d 2.63 (d, J = 4.8 Hz, 3H), 2.65
(d, J = 4.8 Hz, 3H), 8.7–8.9 (br, 1H), 9.1–9.2 (br, 1H); 13C NMR
(100 MHz, DMSO-d6) d 26.3 (CH3), 26.4 (CH3), 110.3 (C), 151.7
(C), 154.3 (C), 156.7 (C); MS (EI) 170 (8), 143 (73), 113 (32), 58
(100), 53 (62). Anal. Calcd for C6H8N4O4: C, 36.00; H, 4.03; N,
27.99%. Found: C, 36.19; H, 4.01; N, 28.26%.
Recrystallized from a mixed solvent of benze◦ne and hexane (1/1).
◦
Colorless solid. Mp 113–115 C (lit.12c 111 C). IR (KBr) 3287,
1655, 1544 cm-1; 1H NMR (400 MHz, CDCl3) d 2.94 (d, J = 5.1 Hz,
3H), 3.27 (dd, J = 17.9, 8.8 Hz, 1H), 3.66 (dd, J = 17.9, 11.5 Hz,
1H), 5.74 (dd, J = 11.5, 8.8 Hz, 1H), 6.6–6.8 (br, 1H), 7.3–7.45 (m,
5H); 13C NMR (100 MHz, CDCl3) d 26.1 (CH3), 41.2 (CH2), 84.6
(CH), 125.9 (CH), 128.6 (CH), 128.8 (CH), 139.6 (C), 153.6 (C),
160.2 (C); MS (FAB) 205 (M++1, 92), 107 (100), 105 (92). HRMS
Calcd for C11H12N2O2: 204.0899. Found: 204.0899.
Cycloaddition of Nitrile Oxide with Dipolarophiles
General Procedure
4,5-Dihydro-3-(N-methylcarbamoyl)-5-propylisoxazole (11b).
To a solution of nitroisoxazolone 5a (86 mg, 0.60 mmol) and
dipolarophile 7 or 10 (3.0 mmol) in acetonitrile (4.5 mL), water
(1.5 mL) was added, and the resultant mixture was stirred at 30 ◦C
for 1 day. After removal of the solvent under reduced pressure, the
residue was subjected to column chromatography on silica gel or
recrystallization to isolate cycloadduct 8 or 11.
Elu◦ted with hexane–AcOEt (50/50). Colorless solid. Mp 60–
1
62 C. IR (KBr) 3297, 1656, 1551 cm-1; H NMR (400 MHz,
CDCl3) d 0.93 (t, J = 7.2 Hz, 3H), 1.3–1.45 (m, 2H), 1.5–1.6 (m,
1H), 1.65–1.75 (m, 1H), 2.85 (dd, J = 17.6, 8.4 Hz, 1H), 2.89 (d, J
= 4.8 Hz, 3H), 3.25 (dd, J = 17.6, 10.8 Hz, 1H), 4.75 (dddd, J =
10.8, 8.4, 6.8, 5.6 Hz, 1H), 6.6–6.8 (br, 1H); 13C NMR (100 MHz,
CDCl3) d 13.8 (CH3), 18.5 (CH2), 26.1 (CH3), 37.2 (CH2), 38.3
(CH2), 83.6 (CH), 153.8 (C), 160.6 (C); MS (FAB) 171 (M++1,
100). HRMS Calcd for C8H14N2O2: 170.1055. Found: 170.1056.
3-(N-Methylcarbamoyl)-5-phenylisoxazole
(8a)12,23
.
Eluted
with hexane–AcOEt (80/20). Pale yellow plates. Mp 199–200 ◦C
◦
(lit.12c 198–199 C). IR (KBr) 3327, 1668 cm-1; 1H NMR
(400 MHz, CDCl3) d 3.04 (d, J = 5.0 Hz, 3H), 6.8–6.9 (br, 1H),
6.97 (s, 1H), 7.46–7.51 (m, 3H), 7.78–7.81 (m, 2H); 13C NMR
(100 MHz, CDCl3) d 26.4 (CH3), 99.3 (CH), 125.9 (CH), 126.7
(C), 129.1 (CH), 130.7 (CH), 159.1 (C), 159.5 (C), 171.5 (C); MS
(EI) 202 (M+, 9), 105 (31), 58 (100). Anal. Calcd for C11H10N2O2:
C, 65.33; H, 4.98; N, 13.86%. Found: C, 65.36; H, 5.01; N, 13.88%.
3-(N -Methylcarbamoyl)-3a,5,6,6a-tetrahydro-4H -cyclopent-
[d]isoxazole (11c). Eluted with hexane–AcOEt (50/50). Color-
◦
less solid. Mp 72–75 C. IR (KBr) 3330, 1655 cm-1; H NMR
(400 MHz, CDCl3) d 1.3–1.45 (m, 1H), 1.65–1.85 (m, 3H), 2.05–
2.15 (m, 2H), 2.89 (d, J = 5.2 Hz, 3H), 3.92 (dd, J = 8.8, 8.8 Hz,
1H), 5.20 (dd, J = 8.8, 4.8 Hz, 1H), 6.5–6.7 (br, 1H); 13C NMR
(100 MHz, CDCl3) d 23.2 (CH2), 26.0 (CH3), 31.5 (CH2), 35.7
(CH2), 51.0 (CH), 89.8 (CH), 155.4 (C), 160.5 (C); MS (FAB) 169
(M++1, 100). Anal. Calcd for C8H12N2O2: C, 57.13; H, 7.19; N,
16.66%. Found: C, 56.95; H, 7.08; N, 16.37%.
1
5-Hydroxymethyl-3-(N-methylcarbamoyl)isoxazole
(8b).
Eluted with hexane–AcOEt (80/20). Colorless plates. Mp 96–
97 ◦C. IR (KBr) 3600–3100 (br), 1671 cm-1; 1H NMR (400 MHz,
CDCl3) d 2.3–2.6 (br, 1H), 3.00 (d, J = 5.2 Hz, 3H), 4.81 (br s, 2H),
1
6.69 (s, 1H), 6.7–6.9 (br, 1H); H NMR (400 MHz, DMSO-d6)
4,5-Dihydro-5-hydroxymethyl-3-(N-methylcarbamoyl)isoxazole
(11d). Recrystallized from benzene. Colorless plates. Mp 85–
d 2.75 (d, J = 5.2 Hz, 3H), 4.60 (dd, J = 6.0, 0.8 Hz, 2H), 5.73
(t, J = 6.0 Hz, 1H), 6.63 (d, J = 0.8 Hz, 1H), 8.6–8.7 (br, 1H);
13C NMR (100 MHz, DMSO-d6) d 26.0 (CH3), 54.8 (CH2), 101.2
(CH), 158.8 (C), 159.1 (C), 174.6 (C); MS (EI) 156 (3), 125 (11),
◦
86 C. IR (KBr) 3500–3200 (br), 1654, 1558 cm-1; 1H NMR
(400 MHz, CDCl3) d 1.6–2.0 (br, 1H), 2.92 (d, J = 5.2 Hz, 3H),
3.15 (dd, J = 18.0, 8.0 Hz, 1H), 3.28 (dd, J = 18.0, 11.2 Hz, 1H),
This journal is
The Royal Society of Chemistry 2011
Org. Biomol. Chem., 2011, 9, 2832–2839 | 2837
©

View Article Online
3.65 (dd, J = 12.4, 4.4 Hz, 1H), 3.84 (dd, J = 12.4, 3.2 Hz, 1H),
4.88 (dddd, J = 11.2, 8.0, 4.4, 3.2 Hz, 1H), 6.4–6.8 (br, 1H); 13C
NMR (100 MHz, CDCl3) d 26.1 (CH3), 34.8 (CH2), 63.3 (CH2),
83.5 (CH), 154.5 (C), 159.1 (C), 160.3 (C); MS (EI) 158 (M+, 1),
85 (10), 58 (100). HRMS Calcd for C6H10N2O3: 158.1522. Found:
158.1528.
NMR (100 MHz, CDCl3) d 14.1 (CH3), 26.2 (CH3), 38.0 (CH2),
62.2 (CH2), 79.3 (CH), 153.5 (C), 159.5 (C), 169.3 (C); MS (FAB)
187 (M++ 1, 100). HRMS Calcd for C8H12N2O4: 200.0797. Found:
200.0799.
4,5-Bis(methoxycarbonyl)-4,5-dihydro-3-(N-methylcarbamoyl)-
isoxazole (11k). Eluted with hexane–AcOEt (20/80). Colorless
1
oil. IR (neat) 3375, 1746, 1674, 1558 cm-1; H NMR (400 MHz,
4,5-Dihydro-5-ethoxymethyl-3-(N -methylcarbamoyl)isoxazole
(11e). Eluted with AcOEt. Colorless granules. Mp 43–44 ◦C. IR
(KBr) 3336, 1663, 1543 cm-1; 1H NMR (400 MHz, CDCl3) d 1.20
(t, J = 7.0 Hz, 3H), 2.91 (d, J = 5.0 Hz, 3H), 3.13 (dd, J = 17.8,
8.0 Hz, 1H), 3.26 (dd, J = 17.8, 11.1 Hz, 1H), 3.55 (d, J = 4.7 Hz,
2H), 3.55 (q, J = 7.0 Hz, 2H), 4.8–4.95 (m, 1H), 6.65–6.8 (br,
1H); 13C NMR (100 MHz, CDCl3) d 15.4 (CH3), 26.4 (CH3), 35.9
(CH2), 67.5 (CH2), 71.4 (CH2), 82.5 (CH), 154.3 (C), 160.7 (C); MS
(FAB) 187 (M++1, 100). HRMS Calcd for C8H14N2O3: 186.1004.
Found: 186.1004.
CDCl3) cis/trans = 93/7, cis-isomer d 2.93 (d, J = 5.2 Hz, 3H),
3.82 (s, 3H), 3.84 (s, 3H), 4.69 (d, J = 6.4 Hz, 1H), 5.33 (d, J
= 6.4 Hz, 1H), 6.5–6.7 (br, 1H), trans-isomer d 2.92 (partially
overlapped with a signal of cis-isomer), 3.76 (s, 3H), 3.79 (s, 3H),
4.72 (d, J = 12.0 Hz, 1H), 5.38 (d, J = 12.0 Hz, 1H); 13C NMR
(100 MHz, CDCl3) d 26.1 (CH3), 53.2 (CH3), 53.4 (CH3), 55.4
(CH), 83.0 (CH), 151.3 (C), 158.3 (C), 167.9 (C), 168.0 (C); MS
(FAB) 245 (M++1, 100). HRMS Calcd for C9H12N2O6: 244.0695.
Found: 244.0694.
5-Acetyl-4,5-dihydro-3-(N-methylcarbamoyl)isoxazole
(11l).
5-Acetylaminomethyl-4,5-dihydro-3-(N-methylcarbamoyl)iso-
xazole (1◦1g). Recrystallized from chloroform. White solid. Mp
169–171 C. IR (KBr) 3308, 1655 (with shoulder), 1597 cm-1; 1H
NMR (400 MHz, CDCl3) d 1.82 (s, 3H), 2.67 (d, J = 4.7 Hz, 3H),
2.91 (dd, J = 17.9, 7.6 Hz, 1H), 3.20 (dd, J = 17.9, 10.9 Hz, 1H),
3.22 (dd, J = 5.7, 5.6 Hz, 2H), 4.72 (ddt, J = 10.9, 7.6, 5.6 Hz,
Recrystallized from a mixed solvent of benzene and hexane (1/1).
Pale yellow solid. Mp 106–108 ◦C. IR (KBr) 3296, 1718, 1656,
1559 cm-1; 1H NMR (400 MHz, CDCl3) d 2.31 (s, 3H), 2.93 (d, J
= 5.0 Hz, 3H), 3.41 (dd, J = 18.2, 12.1 Hz, 1H), 3.52 (dd, J = 18.2,
7.2 Hz, 1H), 5.05 (dd, J = 12.1, 7.2 Hz, 1H), 6.45–6.5 (br, 1H); 13
C
1H), 8.12 (br t, J = 5.7 Hz, 1H), 8.38 (br q, J = 4.7 Hz, 1H); 13
C
NMR (100 MHz, CDCl3) d 26.2 (CH3), 26.3 (CH3), 36.1 (CH2),
85.7 (CH), 153.8 (C), 159.3 (C), 205.1 (C); MS (FAB) 171 (M++1,
100). Anal. Calcd for C7H10N2O3: C, 49.41; H, 5.92; N, 16.46%.
Found: C, 49.13; H, 5.53; N, 16.42%.
NMR (100 MHz, CDCl3) d 23.3 (CH3), 26.6 (CH3), 37.5 (CH2),
42.4 (CH2), 81.5 (CH), 155.0 (C), 160.6 (C), 170.6 (C); MS (FAB)
200 (M++1, 100). HRMS Calcd for C8H13N3O3: 199.0957. Found:
199.0959.
Methanolysis of nitroisoxazolone 5a. A solution of nitroisox-
azolone 5a (72 mg, 0.50 mmol) in methanol (5.0 mL) was stirred
at 30 ◦C for 1 day. After removal of the solvent under reduced
pressure, the reaction mixture was extracted with benzene (10 mL
¥ 3). The organic layer was concentrated, and the residue was
subjected to column chromatography to afford a mixture of 18
and 3d (eluted with hexane–CHCl3 = 2/1, 23 mg, yield of 18; 18%,
yield of 3d; 12%) and nitroenamine 18 (eluted with hexane–CHCl3
= 1/1, 30 mg, 0.23 mmol, yield 46%). Although further purification
of 3d was attempted by column chromatography again, the
impurity could not be removed. The structural determination was
performed by comparing spectral data with those of 3e, which was
prepared from commercially available ethyl nitroacetate and ethyl
isocyanate.
4,5-Dihydro-5-ethoxy-3-(N-methylcarbamoyl)isoxazole (11h).
Eluted with hexane–AcOEt (50/50). Orange plates. Mp 99–
◦
1
101 C. IR (KBr) 3305, 1655, 1090 cm-1; H NMR (400 MHz,
CDCl3) d 1.22 (dd, J = 7.2, 7.2 Hz, 3H), 2.93 (d, J = 4.8 Hz, 3H),
3.13 (dd, J = 18.8, 2.4 Hz, 1H), 3.26 (dd, J = 18.8, 6.8 Hz, 1H),
3.60 (dq, J = 9.2, 7.2 Hz, 1H), 3.87 (dq, J = 9.2, 7.2 Hz, 1H), 5.67
(dd, J = 6.8, 2.4 Hz, 1H), 6.6–6.7 (br, 1H); 13C NMR (100 MHz,
CDCl3) d 15.0 (CH3), 26.1 (CH3), 40.1 (CH2), 64.3 (CH2), 104.9
(CH), 154.3 (C), 159.9 (C); MS (FAB) 173 (M++1, 96), 127 (100).
Anal. Calcd for C7H12N2O3: C, 48.83; H, 7.02; N, 16.27%. Found:
C, 48.70; H, 6.84; N, 16.45%.
3-(N-Methylcarbamoyl)-3a,4,5,6a-tetrahydrofuro[3,2-d]isoxa-
zole (11i). Recrystallized from a mixed solvent of benzene and
hexane (1/1). Colorless solid. Mp 138–139 ◦C. IR (KBr) 3329,
1662, 1557, 1091 cm-1; 1H NMR (400 MHz, CDCl3) d 2.22 (dddd,
J = 8.9, 8.3, 5.1, 5.0 Hz, 1H), 2.40 (dd, J = 13.1, 5.0 Hz, 1H),
2.92 (d, J = 5.0 Hz, 3H), 3.54 (ddd, J = 13.1, 8.9, 5.1 Hz, 1H),
4.04 (dd, J = 8.9, 6.2 Hz, 1H), 4.10 (dd, J = 8.9, 8.3 Hz, 1H),
6.27 (d, J = 6.2 Hz, 1H), 6.7–6.9 (br, 1H); 13C NMR (100 MHz,
CDCl3) d 26.1 (CH3), 29.7 (CH2), 50.8 (CH), 67.0 (CH2), 110.6
(CH), 154.2 (C), 160.0 (C); MS (FAB) 171 (M++1, 100). Anal.
Calcd for C7H10N2O3: C, 49.40; H, 5.92; N, 16.47%. Found: C,
49.26; H, 5.96; N, 16.53%.
1-Methoxy-1-methylamino-2-nitroethene
(18). Colorless
◦
plates. Mp 110–112 C. IR (Nujol) 3327, 1662, 1564 cm-1; H
NMR (400 MHz, CDCl3) d 3.00 (d, J = 5.2 Hz, 3H), 3.88 (s, 3H),
6.67 (s, 1H), 9.6–10.0 (br, 1H); 13C NMR (100 MHz, CDCl3) d
27.3 (CH3), 56.9 (CH3), 97.9 (CH), 165.1 (C); MS (EI) 132 (M+,
100). HRMS Calcd for C4H8N2O3: 132.0535. Found: 132.0531.
Anal. Calcd for C4H8N2O3: C, 36.36; H, 6.16; N, 21.20%. Found:
C, 36.21; H, 6.19; N, 21.53%.
1
Methyl 4-Aza-2-nitro-3-oxopentanoate (3d). Yellow oil. IR
1
(neat) 3325, 1759, 1686, 1568, 1304 cm-1; H NMR (400 MHz,
CDCl3) d 2.94 (d, J = 5.0 Hz, 3H), 3.92 (s, 3H), 5.90 (s, 1H),
7.2–7.5 (br, 1H); 13C NMR (100 MHz, CDCl3) d 27.4 (CH3), 54.9
(CH3), 89.1 (CH), 158.9 (C), 165.1 (C).
4,5-Dihydro-5-ethoxycarbonyl-3-(N-methylcarbamoyl)isoxazole
(11j). Eluted with hexane–AcOEt (50/50). Pale yellow oil. IR
(neat) 3337, 1747, 1666, 1556 cm-1; 1H NMR (400 MHz, CDCl3)
d 1.23 (t, J = 7.1 Hz, 3H), 2.68 (d, J = 4.7 Hz, 3H), 3.34 (dd, J =
17.9, 6.9 Hz, 1H), 3.52 (dd, J = 17.9, 12.1 Hz, 1H), 4.16 (q, J =
Ethyl 4-Aza-2-nitro-3-oxohexanoate (3e). Yellow solid. Mp
45–46 ◦C. IR (melt) 3308, 1755, 1682, 1570, 1304 cm-1; 1H NMR
(400 MHz, CDCl3) d 1.12 (t, J = 7.2 Hz, 3H), 1.35 (dd, J = 7.2,
7.1 Hz, 2H), 5.23 (dd, J = 12.1, 6.9 Hz, 1H), 8.45–8.5 (br, 1H); 13
C
2838 | Org. Biomol. Chem., 2011, 9, 2832–2839
This journal is
The Royal Society of Chemistry 2011
©

View Article Online
7.2 Hz, 3H), 3.40 (dq, J = 7.2, 5.6 Hz, 2H), 4.30–4.35 (m, 2H),
5.77 (s, 1H), 7.0–7.2 (br, 1H); 13C NMR (100 MHz, CDCl3) d 13.7
(CH3), 14.1 (CH3), 35.4 (CH2), 64.2 (CH2), 88.9 (CH), 157.8 (C),
161.5 (C); MS (EI) 204(5), 72 (21). HRMS Calcd for C7H12N2O5:
204.1806. Found: 204.1809.
7 B. B. Snider and Q. Che, Tetrahedron, 2002, 58, 7821.
8 (a) P. A. Harris, A. Jackson and J. A. Joule, Tetrahedron Lett., 1989,
30, 3193; (b) E. Kaji, K. Harada and S. Zen, Chem. Pharm. Bull., 1978,
26, 3254.
9 S. Kanemasa, S. Kaga and E. Wada, Tetrahedron Lett., 1998, 39,
8865.
10 T. Shimizu, Y. Hayashi and K. Teramura, Bull. Chem. Soc. Jpn., 1985,
58, 2519.
11 V. P. Kislyi, A. L. Laikhter, B. I. Ugrak and V. V. Semenov, Russ. Chem.
Bull., 1994, 43, 98.
Computational Methods
All calculations were performed with the Firefly Quantum Chem-
istry Package.28 The DFT with the B3LYP functional29 and the
6-31+G** basis sets were used for the geometry optimization.
No imaginary frequency and one imaginary frequency were
ascertained for each equilibrium geometry and transition state,
respectively. IRC calculation was carried out to check that the
transition state connected reactant and product. The energy was
evaluated at 298 K with the evaluated potential energy and the
evaluated zero-point energy.
12 (a) L. Cecchi, F. De Sarlo and F. Machetti, Chem.–Eur. J., 2008,
14, 7903; (b) F. Machetti, L. Cecchi, E. Trogu and F. De Sarlo,
Eur. J. Org. Chem., 2007, 4352; (c) L. Cecchi, F. De Sarlo and F.
Machetti, Eur. J. Org. Chem., 2006, 4852.
13 R. Paul and S. Tchelitcheff, Bull. Soc. Chim. Fr., 1963, 140.
14 R. Huisgen and M. Christl, Chem. Ber., 1973, 106, 3291.
15 (a) T. Shimizu, Y. Hayashi, H. Shibafuchi and K. Teranuma, Bull.
Chem. Soc. Jpn., 1986, 59, 2827; (b) T. Shimizu, Y. Hayashi, T. Ito and
K. Teramura, Synthesis, 1986, 488.
16 B. S. Huffman, R. A. Schultz and P. J. Schlom, Polym. Bull., 2001, 47,
159.
17 (a) V. N. Yarovenko, S. A. Kosarev, I. V. Zavazin and M. M. Krayushkin,
Russ. Chem. Bull., 2002, 51, 1504; (b) V. N. Yarovenko, S. A. Kosarev,
I. V. Zavazin and M. M. Krayushkin, Russ. Chem. Bull., 1998, 47, 1947.
18 A. Parhi and R. W. Franck, Org. Lett., 2004, 6, 3063.
19 (a) J. Romanski, C. Chpuis and J. Jurczak, Helv. Chim. Acta, 2009, 92,
1056; (b) J. Romanski, J. Jo´zwik, C. Chpuis and J. Jurczak, Helv. Chim.
Acta, 2007, 90, 2116.
20 (a) M. J. Kamlet, J. Org. Chem., 1959, 24, 714; (b) N. Nishiwaki, T.
Nogami, C. Tanaka, F. Nakashima, Y. Inoue, N. Asaka, Y. Tohda and
M. Ariga, J. Org. Chem., 1999, 64, 2160; (c) N. Nishiwaki, Y. Takada,
Y. Inoue, Y. Tohda and M. Ariga, J. Heterocycl. Chem., 1995, 32, 473.
21 (a) M. Tamura, Y. Ise, Y. Okajima, N. Nishiwaki and M. Ariga,
Synthesis, 2006, 3453; (b) N. Nishiwaki, Y. Okajima, M. Tamura, N.
Asaka, K. Hori, Y. Tohda and M. Ariga, Heterocycles, 2003, 60, 303.
22 N. Nishiwaki, M. Nakanishi, T. Hida, Y. Miwa, M. Tamura, K. Hori,
Y. Tohda and M. Ariga, J. Org. Chem., 2001, 66, 7535.
23 S. Higashida, H. Nakashima, Y. Tohda, K. Tani, N. Nishiwaki and M.
Ariga, Heterocycles, 1992, 34, 1511.
Acknowledgements
This work was supported by Kyoto-Advanced Nanotechnology
Network from the Ministry of Education, Culture, Sports, Science
and Technology, Japan. Authors are grateful to Prof. Kiyomi
Kakiuchi, Nara Institute of Science and Technology, for his kind
assistance.
References
1 A. Padwa, W. H. Pearson, E. C. Taylor and P. Wipf, Synthetic
Application of 1,3-Dipolar Cycloaddition Chemistry toward Heterocycles
and Natural Products, Wiley-Interscience (2002).
2 G. Molteni, Heterocycles, 2006, 68, 2177.
3 S. Kanemasa, Sci. Synth., 2004, 19, 17.
4 C. J. Easton, C. M. M. Hughes, G. P. Savage and G. W. Simpson, Cy-
cloaddition Reaction of Nitrile Oxides with Alkenes in Adv. Heterocycl.
Chem., 60, 261, Academic Press (1994).
24 N. Nishiwaki, T. Uehara, N. Asaka, Y. Tohda, M. Ariga and S.
Kanemasa, Tetrahedron Lett., 1998, 39, 4851.
25 R. Nesi, S. Chimichi, F. De Sio, R. Pepino and P. Tedeschi, Tetrahedron
Lett., 1982, 23, 4397.
5 (a) D. Conti, M. Rodriquez, A. Sega and M. Taddei, Tetrahedron Lett.,
2003, 44, 5327; (b) G. P. Moloney, G. R. Martin, N. Mathewa, H.
Hobbs, S. Dodsworth, P.-Y. Sang, C. Knight, M. Maxwell and R. C.
Glen, J. Chem. Soc., Perkin Trans. 1, 1999, 2713.
6 (a) R. E. Sammelson, R. B. Miller and M. J. Kurth, J. Org. Chem.,
2000, 65, 2225; (b) M. G. Leslie-Smith, R. M. Paton and N. Webb,
Tetrahedron Lett., 1994, 35, 9251.
26 R. H. Prager and C. M. Williams, Heterocycles, 1999, 51, 3113.
27 (a) D. J. Woodman, W. H. Cambell and E. F. DeRose, Heterocycles,
1977, 7, 247; (b) D. J. Woodman, P. M. Stonebraker and L. Weiler,
J. Am. Chem. Soc., 1976, 98, 6036.
28 A. A. Granovsky, http://classic.chem.msu.su/gran/gamess/index.html.
29 (a) A. D. Becke, Phys. Rev. A: At., Mol., Opt. Phys., 1988, 38, 3098;
(b) A. D. Becke, J. Chem. Phys., 1983, 98, 5648.
This journal is
The Royal Society of Chemistry 2011
Org. Biomol. Chem., 2011, 9, 2832–2839 | 2839
©