Acid-base-catalysed condensation reaction in water: Isoxazolines and isoxazoles from nitroacetates and dipolarophiles

Article abstract of DOI:10.1002/chem.201102264

Base-catalysed condensation reactions of nitroacetic esters with dipolarophiles to give isoxazole derivatives proceed faster, and often with higher yields, in the presence of water than in organic solvents such as chloroform. Kinetic profiles show that in

Full text of DOI:10.1002/chem.201102264

FULL PAPER
DOI: 10.1002/chem.201102264
Acid–Base-Catalysed Condensation Reaction in Water: Isoxazolines and
Isoxazoles from Nitroacetates and Dipolarophiles
Elena Trogu,[a] Claudia Vinattieri,[a] Francesco De Sarlo,*[a] and Fabrizio Machetti*[b]
Dedicated to Professor Alberto Brandi on the occasion of his 60th birthday
Abstract: Base-catalysed condensation
reactions of nitroacetic esters with di-
polarophiles to give isoxazole deriva-
tives proceed faster, and often with
higher yields, in the presence of water
than in organic solvents such as chloro-
form. Kinetic profiles show that induc-
tion times are greatly reduced when
the reaction is performed “in water” or
“on water”. Any specificity of the base
related to H-bonding ability observed
in chloroform is lost in water: all bases
either organic or inorganic give the
same result that is simply depending on
concentration.
A
0.1 molar ratio of
duct. This is a remarkable example of a
condensation reaction occurring in
water because of irreversible acid-cata-
lysed water elimination. The reaction
has been successfully applied to dipo-
larophiles containing a wide variety of
functional groups, including carboxylic
acids and ammonium salts, under mild
conditions. This new click-style reac-
tion is expected to be compatible with
biological environments.
base to nucleophile gives the best con-
version, whereas addition of one equiv-
alent of base or strong acid prevents
the reaction from occurring. These re-
sults fit into a reaction sequence in
which reversible addition to a dipolaro-
phile is followed by acid-catalysed irre-
versible dehydration of the cycload-
Keywords: cycloaddition · homoge-
neous catalysis · isoxazoles · nitro-
gen heterocycles · water
Introduction
water” reactions.[10] If the products are water insoluble the
reaction work-up is made easier.[11] However, when the
product needs to be extracted from the aqueous solution the
primary benefit of avoiding organic solvents is lost.[12]
Diels—Alder reactions, both catalysed and uncatalysed,[13]
1,3-dipolar cycloaddition reactions,[14] Claisen rearrange-
ments,[15] nucleophilic substitutions or additions,[16] Michael
reactions and aldol-type reactions are among the transfor-
mations that have been successfully carried out in water.
Both the rates and selectivities[17] of reactions have been
shown to be affected by the presence of water relative to
the same reactions in organic solvents. The extensive litera-
ture on organic reactions in water has been the object of
many reviews.[18]
Water is the cheapest and most environmentally benign sol-
vent. It is the medium in which the chemistry of life takes
place.[1] Early studies of the use of water for organic reac-
tions were likely encouraged by these facts. However many
other features of organic reactions carried out in water have
created considerable interest in this subject during the last
30 years.[2,3] In many cases considerable rate enhancements
are observed in water relative to same reactions in organic
solvents.[4] This effect is often caused by the simple presence
of water, because sparingly soluble reagents participate in
the reaction as a separate phase. In these cases stirring is
helpful and a faster reaction of liquid than solid reagents
has been reported.[5] These reactions have been defined as
“on water”[6–9] or “in the presence of water” rather than “in
Isoxazole and its derivatives have received much attention
during the past century.[19] Isoxazoles continue to be used as
intermediates in organic synthesis or in the preparation of
different classes of compounds that have the isoxazole skele-
ton embedded.[20–23]
[a] Dr. E. Trogu, Dr. C. Vinattieri, Prof. F. De Sarlo
Dipartimento di Chimica “U. Schiff”
Universitꢀ di Firenze, Via della Lastruccia 13
50019 Sesto Fiorentino, Firenze, (Italy)
E-mail: fdesarlo@unifi.it
Previous procedures for the synthesis of these heterocy-
cles have been based on the dehydration of primary nitro
compounds to give intermediate nitrile oxides followed by
cycloaddition to dipolarophiles [Eq. (1)].[24,25] To serve the
purpose, we have recently developed an improved protocol
by catalysed condensation of the same nitro compounds
with dipolarophiles [Eq. (2)].[26–31] Whereas the former
method requires anhydrous conditions and dehydrating re-
agents in stoichiometric amounts,[32,33] the latter condensa-
tion reaction in chloroform relies on the acid-catalysed de-
[b] Prof. Dr. F. Machetti
Istituto di Chimica dei Composti Organometallici
del Consiglio Nazionale delle Ricerche
c/o Dipartimento di Chimica “U. Schiff”
Universitꢀ di Firenze, Via della Lastruccia 13
50019 Sesto Fiorentino, Firenze, (Italy)
E-mail: fabrizio.machetti@unifi.it
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hydration of the intermediate cycloadduct.[30] Importantly,
the final irreversible step is compatible with the presence of
water.
Condensation reactions in water require a driving force
capable of shifting the equilibrium in favour of the desired
product. For example, removal of the product in a separate
phase, owing to low solubility. Similarly, a “micellar effect”
has been reported that displaces the equilibria towards the
condensation product, even in aqueous medium.[34,35] In
Equation (2), water elimination with formation of the C=N
double bond provides the driving force for dehydration.
Water elimination from aldoximes to nitriles is well
known,[36,37] whereas only a few examples of water elimina-
tion from N-substituted hydroxylamines have been report-
ed: imines are obtained by thermolysis,[38] with KHSO4,[39] or
under TiIII[40] catalysis.
Results and Discussion
Reaction in water/reaction on water: As reported in our
previous papers,[27,28] ethyl nitroacetate reacts with various
dipolarophiles under base catalysis to afford 3-ethoxycarbo-
nylisoxazolines by a cycloaddition–condensation reaction
process. To date, these reactions have been conveniently
and successfully carried out in chloroform. Many reagents
are only sparingly soluble in water and, as such, water was
disregarded as a reaction medium. However, condensation
reactions of ethyl nitroacetate with several dipolarophiles in
water, regardless of solubility, favourably compare with the
results of the same reactions performed in chloroform.
The extents of conversion of dipolarophiles into products
observed after set times are reported in Table 1.
In the present paper we report the catalysed condensation
reaction of nitroacetic esters with a variety of dipolarophiles
(alkenes or alkynes) in aqueous medium [Eq. (3)]. In this
medium the reaction course and the catalytic system are
modified relative to those in organic solvent.
Ethyl
nitroacetate
(1.06 mmol),
dipolarophile
[2.2.2]octane,
(0.424 mmol) and DABCO (1,4-diazabicyclo
AHCTUNGTRENNUNG
0.0424 mmol) forms only a partially soluble reaction mixture
in 1.4 mL of water, although the same reagents would be
completely soluble in the same volume of chloroform. In
fact, a saturated solution of ethyl nitroacetate in water is
Abstract in Italian: La condensazione tra nitroacetati e dipo-
larofili a derivati isossazolici con catalisi basica ꢀ piꢁ veloce
e spesso dꢂ rese migliori in presenza di acqua che in solventi
organici come il clorofomio. Il tempo di induzione della rea-
zione ꢀ ridotto sensibilmente quando la reazione ꢀ condotta
in sistemi acquosi sia omogenei che eterogenei, come mostra-
to dai profili cinetici. La specificitꢂ della base legata alla sua
capacitꢂ di formare legami ad idrogeno, osservata nella rea-
zione condotta in cloroformio, scompare nella reazione con-
dotta in acqua. In questo solvente ogni base, sia organica che
inorganica, porta agli stessi risultati a paritꢂ di concentrazio-
ne. I migliori risultati si ottengono con un rapporto molare
base/dipolarofilo di 0.1, mentre la reazione non procede per
aggiunta di 1 equiv di base, nꢃ in presenza di acido forte.
Questi risultati sono spiegabili con un pre-equilibrio di ci-
cloaddizione fra nitronato o acido nitronico e dipolarofilo,
seguito da eliminazione irreversibile di acqua con catalisi
acida. Si tratta di un notevole esempio di condensazione in
ambiente acquoso, in virtꢁ dell’eliminazione irreversibile di
acqua catalizzata da acidi. Il processo ꢀ stato applicato con
successo a dipolarofili recanti i piꢁ svariati gruppi funzionali,
tra cui il carbossilico e l’ammonico. Perciꢄ, tenuto conto delle
miti condizioni richieste, si puꢄ pensare di utilizzare la con-
densazione tra esteri nitroacetici e dipolarofili come un
nuovo ed efficiente processo di trasformazione molecolare
compatibile con sistemi biologici.
Table 1. Condensation reactions of ethyl nitroacetate with various dipo-
larophiles under base catalysed conditions. Comparison between water
and chloroform as solvent.
Dipolarophile
Product yield [%][a]
CHCl3
H2O
18 h
18 h
80 h
1
2
3
83
0
0
0
16
57
25
88
52 (64)[b]
4
63 (95)[b]
0
96
5
6
96
69
0
4
91
74
7
61
2
65
8
9
40
0
0
84
61
65 (84)[c]
[a] Spectroscopic yield calculated by 1H NMR after the indicated time.
[b] In parentheses the spectroscopic yield calculated after 66 h. [c] In pa-
rentheses the spectroscopic yield calculated after 80 h.
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Isoxazolines and Isoxazolesf
FULL PAPER
about 0.17m at room temperature. If a base (DABCO,
0.03m) is added, the resulting solubility increases to 0.19m
overall of nitroacetate and its salt (nitronate). These values
are not significantly different at 608C. Therefore, in our re-
action conditions, the excess of nitroacetate gives rise to an
organic layer and the reaction takes place partly in water
and partly under heterogeneous conditions.
(Figure 1, solid circles) or by concentrating each sample at
the time indicated and recording the spectrum of the residue
after dissolution in deuterochloroform (Figure 1, open cir-
cles). The dramatic drop of the induction period and the en-
hanced rate observed is attributed, in part, to the neat reac-
tion, but mainly to the reaction occurring “in water” or “on
water”.
The spectroscopic yields reported in Table 1, observed
after 18 h, are significantly higher in water than in chloro-
form. However, the values in parentheses that refer to
longer reaction times (66 or 80 h) show comparable results
in either media. Kinetic profiles of the reactions under both
conditions provide a deeper insight. The reaction progress
was followed by plotting time versus the conversion of dipo-
larophile to product for two model condensation reactions
with ethyl nitroacetate; the first reaction used a water-solu-
ble dipolarophile (allyl alcohol, solubility> 0.3m) and the
second, used styrene, which is water insoluble (Table 1, en-
tries 1 and 3). The graphs in Figure 1 refer to the reaction
with allyl alcohol and show a very long induction period in
chloroform (solid squares): a 52% spectroscopic yield of cy-
cloadduct 2a is obtained after 10 days. During the induction
period the nitroacetate undergoes partial hydrolytic cleav-
age to give ethanol, carbon dioxide and nitromethane.
When performed neat, the reaction (Figure 1, solid trian-
gles) begins after a 3 h induction period, whereas in the
presence of water the induction time is even shorter and the
reaction is almost complete after 8 h. The conversion in the
presence of water could not be monitored directly by NMR
spectroscopy and was evaluated either by extraction
Figure 2 illustrates the progress of the reaction with sty-
rene. The reaction to form product 3a in the presence of
water (open circles) begins after 6 h and attains 75% con-
Figure 2. Kinetic profiles of reactions of 1a with styrene in CHCl3 (solid
squares) and in water (open circles).
version after 12 h, whereas the reaction in chloroform (solid
squares) requires a much longer induction time (48 h). Com-
plete conversion is not achieved in either reaction owing to
nitroacetate hydrolysis affecting the pH of the medium. This
effect is discussed in more detail later in this article.
The above reactions were carried out in water at 608C
with or without stirring. After 18 h the reaction with allyl al-
cohol reached 76 and 74% conversion with and without stir-
ring, respectively. The reaction with styrene reached 73 and
25% conversion with and without stirring, respectively. We
consider the reaction with allyl alcohol to take place mainly
“in water” because stirring does not significantly modify the
reaction rate. In contrast, stirring improves the reaction with
styrene, therefore we consider this reaction to take place
mainly “on water”.
To obtain accurate kinetic profiles the reactions needed to
be carried out under homogeneous conditions. By perform-
ing the reaction in heavy water (D2O) it could be monitored
directly by NMR spectroscopy. Solutions of methyl nitroace-
tate (0.256m), which is more soluble than the ethyl ester, in
Figure 1. Reaction profiles for the condensation reaction of ethyl nitro-
ACHTUNGTRENNUNGacetate (1a) and allyl alcohol in water or chloroform as solvent or neat.
Reaction in water with extraction in chloroform (solid circles); reaction
in water followed by concentration (open circles); reaction in chloroform
(solid squares) and neat (solid triangles).
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F. Machetti, F. De Sarlo et al.
water, D2O or chloroform were treated with water-soluble
dipolarophiles and DABCO under the same conditions as
those described above. The influence of isotopic composi-
tion of water on condensation reaction of allyl alcohol with
methyl nitroacetate (1b) is illustrated in Figure 3. The kinet-
Figure 4. Condensation reaction of methyl nitroacetate (1b) with allyl al-
cohol catalysed by DABCO at 608C. Effect of solvent on the conversion
of dipolarophile to cycloadduct 2b. Heavy water (solid squares); deutero-
chloroform (open squares).[41]
Figure 3. Condensation reaction of methyl nitroacetate (1b) with allyl al-
cohol catalysed by DABCO at 608C. Effect of solvent isotope composi-
tion on the conversion of dipolarophile to cycloadduct. Heavy water
(solid squares); heavy water/water 1:2 (open squares); heavy water/water
1:1 (open circles).
ic profiles for the reaction in D2O (solid squares) and in
mixtures of D2O and H2O (ratio 1:1, open squares; ratio 1:2,
open circles), obtained by direct NMR monitoring, did not
show significant differences due to the solvent isotope com-
position. Evaluation of NMR spectroscopic signals is more
accurate in D2O than in the presence of water. In this case a
constant rate was seen after less than 1 h and conversion
almost complete within 2.5 h.
The reaction profiles of 1b with allyl alcohol (Figure 4)
and with its water-soluble homologues (Figure 5) in D2O
and CDCl3 are dramatically different. In deuterochloroform
complete conversion is only achieved after 10 days following
a very long induction period. Similarly, for the homologues
of allyl alcohol, conversion is completed in water within 3 h.
After the same time in chloroform, no product is observed
under the same conditions (Figure 5).
Base catalysis: The model reactions with allyl alcohol and
with styrene, carried out under various experimental condi-
tions, gave the results reported in Table 2. Without the addi-
tion of base, no reaction is observed in the “neat” mixture
of nitroacetate with styrene, whereas low conversion was
found in the neat reaction with allyl alcohol (Table 2,
entry 4). In the case of allyl alcohol, the hydroxy group
might be providing a small catalytic effect. On addition of
water both reactions were successful, although long reaction
times were required (Table 2, entries 6, 7 and 8). Addition
of a catalytic amount of base (DABCO) resulted in a faster
Figure 5. Condensation reaction of methyl nitroacetate (1b) with 3-
buten-1-ol (circles) and 4-penten-1-ol (triangles) catalysed by DABCO at
608C. Effect of solvent on the conversion of the dipolarophiles to the cy-
cloadducts 4b and 5b, respectively. Heavy water (solid markers) deutero-
chloroform (open markers).
condensation reaction under neat conditions as well as with
water.[42] The conversion enhancement caused by both base
and water is dramatic for the “in water” reaction of allyl al-
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Isoxazolines and Isoxazolesf
FULL PAPER
Table 2. Condensation reaction of ethyl nitroacetate with allyl alcohol or
styrene either neat or in water and various bases.
same model reactions with allyl alcohol and with styrene
shows a maximum conversion at 0.1 equivalents of base
after 18 h (Figure 6).
Conditions
t
2a
3a
[h]
Yield
Yield
[%][a]
[%][a]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
neat, 608C
neat, 608C
neat, 1008C
neat, 1008C
water, 608C
water, 608C
water, 608C
water, 1008C
18
0
0
0
10
0
0
0
0
0
0
0
24
6
62
52
0
73
75
72
72
69
64
68
63 (0)
0
65
18
65
18
48
216
18
18
18
95
18
18
18
18
18
18
18
18
18
18
10
35
43
49
83
35
74
83
70
79
80
68
67
66 (0)
0
neat, DABCO 0.1 equiv, 608C
water, DABCO 0.1 equiv, 608C
water, DABCO 0.1 equiv, 308C
water, pyridine 0.1 equiv, 608C
water, triethylamine 0.1 equiv, 608C
water, butylamine 0.1 equiv, 608C
water, piperidine 0.1 equiv, 608C
water, NaOH 0.1 equiv, 608C
water, Na2CO3 0.1equiv, 608C
water, KF 0.1 equiv, 608C
phosphate buffer solution,[b] 608C
HCl solution,[c] 608C
Figure 6. Profiles of the reaction between ethyl nitroacetate (1a) and
allyl alcohol (open circles) or styrene (solid squares). The data shows the
calculated yield after 18 h depending on the amount of sodium hydroxide
used in the reaction.
The reactions with 1 equivalent or more of sodium hy-
droxide failed due to the lack of or drop in acidity necessary
for water release. In buffer solution (0.1m, pH 7) corre-
sponding to 0.33 equivalent of base the result was not signif-
icantly modified (Table 2, entry 19).
HCl solution,[c] DABCO 0.1 equiv, 608C
0
0
[a] Spectroscopic yield calculated by 1H NMR with an internal standard.
[b] 0.1m (0.33 equiv) phosphate. In parentheses 0.5m (1.66 equiv) phos-
phate buffer, (pH 7.0). [c] 0.6m (pH<1).
By using phosphate buffer (0.5m) corresponding to
1.66 equivalent of base, the condensation reaction is pre-
vented (Table 2, entry 19, values in parentheses). We may
conclude therefore that a catalytic amount of base is re-
quired for the condensation reaction to take place. Howev-
er, the success of the reaction rests on the excess of nitro-
cohol (Table 2, entry 10) and occurs even at a lower temper-
ature (Table 2, entry 11). The base specificity observed in
chlorofom[27] is lost in reactions carried out either “in water”
or “on water”. The results of the reactions are scarcely af-
fected irrespective of whether DABCO, pyridine, triethyl-
AHCTUNGTREGUNaNN cetate that keeps the pH of the medium low enough to
A
allow the release of water in the final irreversible, rate-de-
termining step (Scheme 1).
(0.1 equiv with respect to dipolarophile: Table 2, entries 10–
18). On the other hand, condensation reactions are observed
in water alone (though slower, Table 2, entries 6 and 7), al-
though no reaction takes place in the presence of excess hy-
drochloric acid (Table 2, entries 20 and 21), in which the
concentration of nitronate becomes negligible. The effect of
a phosphate solution (Table 2, entry 19) is discussed below.
Slow reactions, like the condensation reaction with sty-
rene (Figure 2), do not achieve complete conversion of the
dipolarophile owing to the parallel hydrolysis of nitroacetate
to nitroacetic acid (pKa =1.63).[43] When the reaction was
performed in D2O at 608C with 0.1 equivalents of base,
0.1 equivalents of nitroacetate are hydrolysed after 12 h;
with exceedingly long reaction times, nitromethane was also
detected as a result of cleavage of nitroacetic acid.[44–46]
Furthermore, the reactivity of dipolarophiles with ethyl
nitroacetate depends on the amount of added base (the
excess of nitroacetate forms as a separate phase and acts as
a buffer, to some extent, for the aqueous solution). For the
Synthetic applications: We then tested the scope of the reac-
tion. Comparison between dipolarophiles with the same
functional group, but different chain lengths, indicates that
the water solubility of the dipolarophile does not affect the
efficiency of the reactions (Table 3, entries 1–8). Both short-
and long-chain dipolarophiles give the cycloadducts in good
to excellent yield.
By using the reaction conditions described above the
scope of the reaction was explored. Challenging substrates,
which may interfere both with the catalytic system and ni-
troacetate reagents, were included (Tables 3 and 4). Good
chemoselectivity and broad functional group tolerance on
the dipolarophiles was noted when screening condensation
reactions of nitroacetates to give 4,5-dihydroisoxazoles and
isoxazoles. Compounds that contained a labile proton such
as carboxylic acids and ammonium salts were also included.
Moreover, in view of the mild conditions, this reaction
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F. Machetti, F. De Sarlo et al.
Table 4. Condensation reaction of nitroacetates with alkynes bearing var-
ious functional groups (FG).[a]
FG
n
Product
Yield [%][b]
1
2
OH
Ph
1
0
21a
22a
77
88
[a] See the Experimental Section for details. [b] Analytically pure, isolat-
ed product yield (yields were not optimised).
Similarly phenylacetylene reacts “on water” to give an ex-
cellent product yield.
Alcohols and phenol (see Table 3, entries 2, 3, 10; Table 4
entry 1): Both 3-buten-1-ol and 10-undecen-1-ol react in so-
lution to give excellent results. However, 2-allylphenol,
which is sparingly soluble in water, reacts to give a fair prod-
uct yield. Similarly, propargyl alcohol affords 3-carbethoxy-
5-hydroxymethylisoxazole in fair yield.
Scheme 1. Reaction mechanism between dipolarophile and nitroacetate.
Table 3. Condensation reaction of nitroacetates with alkenes bearing var-
ious functional groups (FG).[a]
Nitro, bromo, ether, methylthio and cyanide groups (see
Table 3, entries 13, 15, 16, 17 and 18, respectively): When the
functional group is unconjugated with the reacting double
bond fair to excellent results are obtained. Note the chemo-
selective behaviour shown when two nitro groups are pres-
ent (Table 3, entry 13). Nitroalkanes are unreactive under
these reaction conditions.
FG
n
Product
Yield [%][b]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
H
OH
OH
C(Me)2CHO
CHO
CO2H
CO2H
CO2H
C6H5
2-OH-C6H4
NH3
10
2
9
1
8
1
1
8
1
1
2
2
3
2
2
1
1
3
6a
4a
7a
8a
74
84
93
73
90
81
91
83
62
70
89
88
95
94
74
46
53
99
Aldehydes and ketones (see Table 3, entries 4, 5 and 14): The
aldehyde 2,2-dimethylheptenal, which is sparingly soluble in
water, reacts with good results. 1-Undecenal, which is
almost insoluble, reacts very well “on water”. It should be
noted that cycloaddition reactions with nitro compounds as
precursors of dipoles on unprotected olefinic aldehydes
have been rarely reported.[49] Usually, to overcome lower
yields, the aldehyde function is protected prior to cycloaddi-
tion[50] or masked with a suitable functional group.[20c,51] 1-
Hexen-5-one reacts with ethyl nitroacetate in excellent yield
(Table 3, entry 14).
9a
10a
10b
11a
12a
13a
14a
14b
15a
16a
17a
18b
19a
20a
+
+
NH3
NO2
COMe
Br
OEt
SMe
CN
The use of water can expand the scope of this reaction to
give excellent results with carboxylic acids and amines.
[a] See the Experimental Section for details. [b] Analytically pure, isolat-
ed product yield (yields were not optimised).
Carboxylic acids (see Table 3, entries 6–8): Carboxylic acids
give condensation products in excellent yields irrespective
of chain length and solubility (Table 3, entry 6 vs. entry 8). It
is worth noting that dipolarophiles bearing carboxylic acids
have never been used in a dehydration reaction to give the
intermediate nitrile oxides. Isoxazole carboxylic acids are
generally prepared from the corresponding esters as inter-
mediates.[52]
might prove valuable in a biological context.[47,48] The sub-
strates reported in Tables 3 and 4 mainly react either “in”
and/or “on” water depending on their solubility.
Hydrocarbons (see Table 3, entries 1, 9; Table 4 entry 2): 1-
Dodecene, and allylbenzene are insoluble in water, there-
fore these reactions are considered to occur “on water”.
Amines (see Table 3, entries 11 and 12):. Amines react as am-
monium salts without the need of protection. 4-Amino-1-
butene undergoes the reaction as the hydrochloride salt.
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Isoxazolines and Isoxazolesf
FULL PAPER
The alkylammonium group is a weaker acid than the nitro-
acetic ester, thus the amount of nitronate is not affected.
However, conversion is only partial when reacting the free
amine. The result is not improved when methyl nitroacetate
(1b), which is more soluble in water, is used (Table 3,
entry 12). It is worth noting that dipolarophiles bearing un-
protected amino groups have never been used to prepare
isoxazoles from nitrocompounds. Preparation of isoxazolines
from the nitrile oxides generated from nitro compounds has
been rarely reported even with protected amines[53] or com-
pounds obtained through functional group interconver-
sion.[54]
ratio greater than 1.[32,55] Here the aim is to favour the cyclo-
addition reaction by reducing as much as possible dimerisa-
tion of nitrile oxide to furoxan. A synthesis involving a silyl
nitronate intermediate would require an additional step.[56]
Finally, in view of the mild aqueous conditions, compati-
ble with a biological environment, this condensation can be
envisaged as a new protocol reminiscent of the analogous
“click process” with azides.[47b,57]
Experimental Section
General methods: Melting points were determined in capillaries with a
Bꢂchi 510 apparatus and are uncorrected. Chromatographic separations
were performed on silica gel 60 (40–6.3 mm) with analytical grade sol-
vents, driven by a positive pressure of air; Rf values refer to TLC (visual-
ised with UV light and/or by dipping the plates into a solution of per-
manganate followed by heating with a heat gun). TLC was carried out on
alumina backed plates coated with 25 mm silica gel (Merck F254) with the
same eluant as indicated for the column chromatography. For gradient
column chromatography Rf values refer to the more polar eluant. Solvent
removal was performed by evaporation under reduced pressure at room
Conclusion
The success of the reported condensation reaction depends
on a number of parameters.
*
A catalytic amount of base is required to produce a con-
centration of adduct that is sufficient to push the final ir-
reversible step to release water.
The elimination of water requires a catalytic amount of
acid. This is ensured by using an excess of nitroacetate.
1
temperature. H and 13C NMR spectra were recorded with a Varian Mer-
1
curyplus 400 spectrometer (operating at 400 MHz for H and 100.58 MHz
for 13C) unless otherwise stated. The 1H NMR data are reported as (s=
singlet, d=doublet, t=triplet, m=multiplet or unresolved, br=broad
signal, coupling constant(s) in Hz, integration). Multiplicity of the
13C NMR signals and assignments were determined by means of gHMQC
and gHMBC experiments. Chemical shifts were determined relative to
the residual solvent peak (CHCl3: 7.24 ppm for 1H NMR and 77.0 ppm
*
*
However, if the reaction is exceedingly slow yields are
not quantitative because hydrolysis of nitroacetate com-
petes with the condensation reaction. The resulting nitro-
acetic acid (pKa =1.63) reacts with the catalyst—in these
cases yields are not quantitative for this reason, rather
than due to consumption of nitroacetate;
With very long reaction times decomposition of nitroace-
tate occurs resulting in cleavage of the nitroacetic acid to
give carbon dioxide and nitromethane.
1
for 13C NMR; H2O: 4.74 ppm for H NMR). Chemical shifts for 13C NMR
in D2O are relative to CH3CN (1.47 ppm) as internal reference. EI (elec-
tron impact) mass spectra were recorded with a Shimadzu QP5050 A
quadrupole-based mass spectrometer (direct introduction unless other-
wise stated, at ionising voltage of 70 eV). ESI (electrospray ionisation)
mass spectra were recorded with a ThermoFisher LCQ-Fleet ion trap in-
strument and spectra were registered with either ESI+ or ESIÀ technique.
Ion mass/charge ratios (m/z) are reported as values in atomic mass units
followed by the intensities relative to the base peak in parentheses. IR
*
*
The excess of nitroacetate, which sits as a separate phase,
helps the aqueous solution to be buffered; hydrolysis is
slower than in solution.
Heating the reaction mixture is favourable for the con-
spectra were recorded with a Perkin–Elmer 881 spectrophotometer;
bands are characterised as broad (br), strong (s), medium (m) and weak
(w). Elemental analyses were recorded with an Elemental Analyser
Perkin–Elmer 240C apparatus.
*
densation reaction, particularly when this reaction is in
competition with the conjugate addition.[31] This suggests
that the release of the water is the rate-determining step
and not the cycloaddition. However, at 1008C the decom-
position of nitroacetate is detrimental.
Solubility in water at 258C of dipolarophiles (m):[58] Very soluble: 2-
propen-1-ol (allyl alcohol)[59] (2.13), 2-propyn-1-ol (propargyl alcohol)[60]
(3.62), 3-buten-1-amine (1.04); Soluble: 3-buten-1-ol (0.82), 4-penten-1-ol
(0.45), 3-butenoic acid (0.83), 5-hexenenitrile (0.13), 3-ethoxy-1-propene
(allyl ethyl ether)[61] (0.29), 5-hexen-2-one (0.19), allyl methyl sulphide
(0.20); Slightly soluble: 2,2-dimethyl-4-pentenal (0.028), 2-(prop-2-enyl)-
phenol (0.022), 5-nitropent-1-ene (0.074); Sparingly soluble: styrene[62]
(2.98ꢃ10À3), 10-undecenal (6.9ꢃ10À4), 10-undecen-1-ol (3.6ꢃ10À4), 1-
hexene (4.98ꢃ10À4), phenylacetylene (4.2ꢃ10À3), 1-dodecene (4.1ꢃ10À8),
allylbenzene (1.0ꢃ10À3), 4-bromobut-1-ene (6.8ꢃ10À3), norbornene (2.4ꢃ
10À3), 10-undecenoic acid[63] (1.8ꢃ10À3).
The best results are obtained by using an excess of nitro-
ACHTUNGTRENNUNGacetate and 0.1 equivalents of any base. Since the reaction
requires much shorter induction periods than in organic sol-
vents, hydrolysis of nitroacetate, in most cases, does not
limit the yield of the condensation reaction. The condensa-
tion reactions occur easily in water with dipolarophiles con-
taining acidic protons such as carboxylic acids and ammoni-
um salts. Importantly, the synthesis of isoxazole derivatives
from nitro compounds containing these functional groups as
well as aldehydes has been rarely reported to date, and
often with poor results. This method requires a ratio of dipo-
larophile to reagent of less than 1. Previous methods, based
on nitrile oxides as intermediates (either from nitro com-
pounds or from hydroxamoyl chlorides), have required a
All compounds were named with Autonomꢄ (Beilstein Information Sys-
tems) and modified where appropriate.
Materials: All alkenes and alkynes are liquid at room temperature
except norbornene (m.p. 44–468C) and but-3-enylammonium chloride
(m.p. 176–1808C) . Commercially available (Lancaster and Aldrich) ethyl
nitroacetate (1a), methylnitroacetate (1b), organic bases, olefins and al-
kynes were used as supplied. CHCl3 (ethanol free) was filtered through a
short pad of potassium carbonate just before use. Water (deionised) was
twice distilled from KMnO4 before use.
Condensation reaction of ethyl nitroacetate with different dipolarophiles
under base catalysis—comparison between water and chloroform
(Table 1): A mixture of ethyl nitroacetate (1.06 mmol), alkene or alkyne
Chem. Eur. J. 2012, 18, 2081 – 2093
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
2087

F. Machetti, F. De Sarlo et al.
(0.424 mmol), DABCO (0.0424 mmol) and water or chloroform (1.4 mL)
was heated to 608C with vigorous stirring in a sealed tube. After a given
amount of time, the reaction mixture was concentrated and the crude res-
idue was dissolved in deuterochloroform with 2,4-dimethoxy-acetophe-
none (14–21 mg, 0.078–0.12 mmol) as the internal standard and the
1H NMR spectra was recorded. The spectroscopic yields and reaction
times are reported in Table 1. Integration of the 3’ and 5’-proton signals
of the internal standard (m, 6.40–6.58) and the signal of one proton (4-H
or 5-H) of the cycloadduct on the NMR spectra were used to calculate
the spectroscopic yields. The following signals were used: Table 1,
entry 1: 4.88 ppm (m, 5-H); entry 2: 4.98 ppm (m, 5-H); entry 3: 3.20 ppm
(dd, 4-H); entry 4: 4.64 ppm (d, CHON); entry 5: 4.80 ppm (m, 5-H);
entry 6: 6.81 ppm (s, 4-H); entry 7: 6.62 ppm (brs, 4-H); entry 8:
3.21 ppm (dd, 4-H) or 4.67 ppm (m, 5-H); entry 9: 3.20 ppm (dd, 4-H) or
2.81 ppm (dd, 4-H)].
culated by integrating one of the olefinic proton signals of allyl alcohol
(6.34–6.48 ppm, m, 2H) and the 5-H proton signal for the cycloadduct
2b. The spectroscopic yield of the final reaction mixture appeared to be
quantitative, thus the formation of the cycloadduct was assumed to be
the only process involving allyl alcohol. Signals for Me2SO2 were record-
ed as: 1H NMR (D2O, 26 8C): d=3.16 ppm; 1H NMR (D2O, 60 8C): d=
3.52 ppm.
Methyl ester of 5-hydroxymethyl-4,5-dihydroisoxazole-3-carboxylic acid
(2b): 1H NMR (D2O, 26 8C): d=3.11 (dd, J=8.0 and 18.0 Hz, 1H; 4-H),
3.39 (dd, J=11.6 and 18.0 Hz, 1H; 4-H), 3.66–3.71 (m, 2H; CH2OH),
1
3.91 (s, 3H; OCH3), 5.01–5.08 ppm (m, 1H; 5-H); H NMR (D2O, 60 8C):
d=3.47 (dd, J=8.4, 18.0 Hz, 1H; 4-H), 3.74 (dd, J=11.2, 18.0 Hz, 1H; 4-
H), 4.05 (dd, J=5.2, 12.4 Hz, 1H; CH2OH), 4.18 (dd, J=3.6, 12.4 Hz,
1H; CH2OH), 4.28 (s, 3H; OCH3), 5.35–5.43 ppm (m, 1H; 5-H).
Progress of the condensation reaction of methyl nitroacetate with alco-
holic dipolarophiles in water or in chloroform (homogeneous solutions;
Figures 4 and 5)
Condensation reaction of allyl alcohol with ethyl nitroacetate in water,
chloroform or neat (Figure 1), and condensation of styrene with ethyl ni-
troacetate in water and chloroform (Figure 2)
Preparation of samples: DABCO (2.4 mg, 0.0212 mmol), methyl nitroace-
tate 1b (63 mg, 0.529 mmol), dipolarophile (0.212 mmol: allyl alcohol
(12 mg); 3-buten-1-ol (15 mg), 4-penten-1-ol (18 mg)) and Me2SO2 (5.0–
8.0 mg, internal standard) were mixed with heavy water (2.24 g, 2 mL) or
deuterochloroform (3.0 g, 2 mL), freshly filtered through K2CO3, at room
temperature. A clear solution was obtained after stirring a few minutes
at room temperature and an aliquot (550 mL) was transferred to a
septum-sealed 5 mm NMR tube set to spin (20 Hz) in the probe of the
spectrometer maintained at 608C. After a few hours, the reactions in
heavy water were complete, whereas those in deuterochloroform, which
were subject to very long induction periods, were maintained in a ther-
mostatic bath at 608C and checked at appropriate time intervals.
CDCl3
Sample preparation: Reaction mixtures were prepared by dissolving
DABCO (4.8 mg, 0.0425 mmol), ethyl nitroacetate (141 mg, 1.062 mmol),
allyl alcohol (24 mg, 0.424 mmol) or styrene (44 mg, 0.424 mmol), and
(CH3)2SO2 (11–15 mg, 0.1169–0.1594 mmol) as the internal standard in
CDCl3 (1.4 mL, freshly filtered through K2CO3). A sample from each re-
action (550 mL) were transferred to a septum-sealed NMR spectroscopy
tube, spinning (20 Hz) in the probe of the spectrometer, and the spectra
were recorded at 608C. Duplicate reactions were run if unclear results
were obtained.
Spectroscopic yield: 1H NMR spectra were recorded at intervals of 30 or
60 min for each reaction and the spectroscopic yields were calculated by
integrating the CH3 protons signals (2.93 ppm) of the internal standard
and the 4-H protons signals of cycloadduct 2a (3.05–3.28 ppm, m, 2H) or
cycloadduct 3a (3.20 ppm, dd, 1H).
1
Spectroscopic yield: H NMR spectra for the D2O reaction were recorded
at time intervals of 15 min until no further spectral changes were ob-
served. The extent of conversion was calculated by integrating one of the
olefinic protons signals of the dipolarophile (allyl alcohol 6.34–6.48 ppm,
m, 2H; 3-buten-1-ol 5.48–5.58 ppm, m, 2H; 4-penten-1-ol 6.4 ppm, m,
1H) and the 5-H proton signal of the cycloadducts 2b, 4b and 5b. The
spectroscopic yield of the final reaction mixture appeared to be quantita-
tive, thus the formation of the cycloadducts was assumed to be the only
process involving the dipolarophiles.
H2O
Preparation of sample: Reaction mixtures (without internal standard)
were prepared as above but with H2O (1.4 mL) as solvent. The mixtures
were stirred vigorously and maintained at 608C in a thermostatic bath in
sealed tubes .
Methyl ester of 5-(2-hydroxyethyl)-4,5-dihydroisoxazole-3-carboxylic acid
(4b): 1H NMR (D2O, 26 8C): d=1.88–2.07 (m, 2H; CH2C-5), 3.05 (dd, J=
8.0, 18.0 Hz, 1H; 4-H), 3.44 (dd, J=11.2 and 18.0 Hz, 1H; 4-H), 3.76 (td,
J=1.2, 6.0 Hz, 2H; CH2OH), 3.91 (s, 3H, OCH3), 5.02–5.11 ppm (m, 1H;
5-H); 1H NMR (D2O, 60 8C): d=2.23–2.43 (m, 2H; CH2C-5), 3.39 (dd,
J=8.4, 18.0 Hz, 1H; 4-H), 3.78 (dd, J=10.8, 18.0 Hz, 1H; 4-H), 4.09 (t,
J=6.4 Hz, 2H; CH2OH), 4.27 (s, 3H; OCH3), 5.35–5.45 ppm (m, 1H; 5-
H).
Spectroscopic yield: At appropriate time intervals, each reaction mixture
was either extracted into CDCl3 (3ꢃ0.6 mL) or concentrated and the res-
idue dissolved in CDCl3 and 2,4-dimethoxy-acetophenone (14–21 mg,
0.078–0.12 mmol) added as internal standard. The 1H NMR spectra were
then recorded and the spectroscopic yields calculated as described above.
Neat
Preparation of samples. Reaction mixtures were prepared by mixing
DABCO (4.8 mg, 0.0425 mmol), ethyl nitroacetate (1a) (141 mg,
1.062 mmol) and allyl alcohol (24 mg, 0.425 mmol) in sealed tubes at
608C under stirring.
Methyl ester of 5-(3-hydroxypropyl)-4,5-dihydroisoxazole-3-carboxylic
acid (5b): 1H NMR (D2O, 26 8C): d=1.55–1.65 (m, 4H; CH2CH2C-5),
3.00 (dd, J=8.4, 18.0 Hz, 1H; 4-H), 3.40 (dd, J=11.2, 18.0 Hz, 1H; 4-H),
3.66 (t, J=6.4 Hz, 2H; CH2OH), 3.91 (s, 3H; OCH3), 4.94–5.40 ppm (m,
1H; 5-H); 1H NMR (D2O, 60 8C): d=1.92–2.20 (m, 4H; CH2CH2C-5),
3.34 (dd, J=8.4, 18.0 Hz, 1H; 4-H), 3.75 (dd, J=11.2, 18.0 Hz, 1H; 4-H),
4.00 (t, J=6.4 Hz, 2H; CH2OH), 4.27 (s, 3H; OCH3), 5.29–5.39 ppm (m,
1H; 5-H).
Spectroscopic yield: Every hour one reaction mixture was dissolved in
CDCl3 (1 mL). 2,4-Dimethoxy-acetophenone (14–21 mg, 0.078–
1
0.12 mmol) was added as an internal standard and the H NMR spectrum
was recorded. The spectroscopic yields were calculated as described
above.
Effect of water isotope composition (Figure 3): Reactions were run in
septa-sealed 5 mm NMR tubes spinning (20 Hz) in the probe of the spec-
trophotometer at 608C.
Spectroscopic yield: The conversion of the reactions in CDCl3 was calcu-
lated, similarly to the experiments in D2O, by integrating one of the ole-
finic proton signals of the dipolarophile (allyl alcohol at 278C 5.92–
6.02 ppm, m, 1H and at 608C 5.93–6.03 ppm, m, 1H; 3-buten-1-ol at
278C 5.70–5.83 ppm, m, 1H and at 608C 5.73–5.83 ppm, m, 1H; 4-
penten-1-ol 5.74–5.86 ppm, m, 1H) and the 5-H proton signal of the cy-
cloadducts 2b, 4b and 5b. Signals for Me2SO2 were recorded as:
1H NMR (CDCl3, 278C): d=2.94 ppm; 1H NMR (CDCl3, 608C): d=
2.93 ppm.
Preparation of samples: DABCO (2.4 mg, 0.0212 mmol), methyl nitroace-
tate (1b) (63 mg, 0.529 mmol), allyl alcohol (12 mg, 0.212 mmol) and
Me2SO2 (5.1–5.5 mg) as internal standard, were dissolved in heavy water
(2.24 g, 2.00 mL) or heavy water (1.12 g, 1.00 mL) and water (1.00 g,
1 mL), or heavy water (0.762 g, 0.68 mL) and water (1.32 g, 1.32 mL). A
clear solution was obtained after stirring a few minutes at room tempera-
ture and a portion (550 mL) was transferred to an septum-sealed 5 mm
NMR tube set to spin (20 Hz) in the probe of the spectrometer main-
tained at 608C. 1H NMR spectra were recorded at intervals of 15 min
until no further spectral changes were observed. The conversion was cal-
Methyl ester of 5-hydroxymethyl-4,5-dihydroisoxazole-3-carboxylic acid
1
(2b): H NMR (CDCl3, 278C): d=2.22 (brs, 1H; OH), 3.08–3.26 (m, 2H;
4-H), 3.61 (dd, J=4.4, 12.4 Hz, 1H; CHOH), 3.83 (dd, J=3.2, 12.4 Hz,
1
1H; CHOH), 3.84 (s, 3H; OCH3), 4.85–4.92 ppm (m, 1H; 5-H); H NMR
2088
www.chemeurj.org
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2012, 18, 2081 – 2093

Isoxazolines and Isoxazolesf
FULL PAPER
(CDCl3, 608C): d=2.21 (brs, 1H; OH), 3.07–3.24 (m, 2H; 4-H), 3.63 (dd,
J=4.4, 12.4 Hz, 1H; CHOH), 3.82 (dd, J=3.2, 12.4 Hz, 1H; CHOH),
3.84 (s, 3H; CH3O), 4.83–4.90 ppm (m, 1H; 5-H).
As a reaction mixture: (CH3)2SO2 (16.7 mg) as internal standard and
DABCO (2.4 mg, 0.03m) were dissolved in heavy water (0.7 mL). This so-
lution was saturated with ethyl nitroacetate (1a) and the mixture was
transferred to a septum-sealed 5 mm NMR tube and placed in the probe
of the spectrometer at 268C. The 1H NMR spectra were recorded and
the amount of dissolved 1a was calculated by integrating the CH3 proton
signal of the internal standard (d=3.16 ppm, s, 6H) and the CH2O
proton signal for 1a (d=4.22 ppm, q, 2H) at 268C. The concentration of
1a was calculated to be 0.19m. A pH of 4.4 for this solution is in agree-
ment with the pKa value (5.82)[64] of 1a. The concentration of 1a was cal-
culated by using the procedure described above, at 608C to be 0.22m.
Methyl ester of 5-(2-hydroxyethyl)-4,5-dihydroisoxazole-3-carboxylic acid
(4b): The spectroscopic yield for this product was calculated as 54%
after 66 h and 79% after 5 days (not reported in Figure 5). 1H NMR
(CDCl3, 278C): d=1.79–1.88 (m, 1H; CH2C-5), 1.90–2.00 (m, 1H; CH2C-
5), 2.25 (brs, 1H; OH), 2.91 (dd, J=8.4, 17.6.0 Hz, 1H; 4-H), 3.28 (dd,
J=11.0, 17.6 Hz, 1H; 4-H), 3.75–3.79 (m, 2H; CH2OH), 3.83 (s, 3H;
CH3O), 4.91–5.01 ppm (m, 1H; 5-H); 1H NMR (CDCl3, 608C): d=1.81–
1.90 (m, 1H; CH2C-5), 1.92–2.01 (m, 1H; CH2C-5), 2.04 (brs, 1H; OH),
2.91 (dd, J=8.4, 17.6.0 Hz, 1H; 4-H), 3.28 (dd, J=11.0, 17.6 Hz, 1H; 4-
H), 3.76–3.80 (m, 2H; CH2OH), 3.84 (s, 3H; OCH3), 4.90–4.99 ppm (m,
1H; 5-H).
General preparation method for the products reported in Tables 3 and 4:
A solution of NaOH (4.24m, 0.010 mL, 0.0424 mmol) was added to a
mixture of nitroacetic ester 1a (141 mg, 1.06 mmol), or 1b (126.2 mg,
1.06 mmol), dipolarophile (see individual reactions below) and water
(1390 mg) and the mixture vigorously stirred in a sealed tube at 608C for
the indicated time. The reaction mixture was concentrated and the resi-
due was subject to flash chromatography on silica gel to give the desired
products. Different work-up were followed for 10a, for 10b, for 14a, for
14b and for 16a.
Methyl ester of 5-(3-hydroxypropyl)-4,5-dihydroisoxazole-3-carboxylic
acid (5b): Maximum conversion for this reaction was reached after 5
days and resulted in 50% spectroscopic yield (not reported in Figure 5).
1H NMR (CDCl3, 278C): d=1.65–1.75 (m, 4H; CH2CH2C-5), 2.82 (dd,
J=8.4, 17.6 Hz, 1H; 4-H), 3.24 (dd, J=10.8, 17.6 Hz, 1H; 4-H), 3.65 (t,
J=5.6 Hz, 2H; CH2OH), 3.84 (s, 3H; OCH3), 4.78–4.88 ppm (m, 1H; 5-
H).
Condensation reaction of ethyl nitroacetate with 1-dodecene to give
ethyl 5-decyl-4,5-dihydro-3-isoxazolecarboxylate (6a): The reaction of 1-
dodecene (71.4 mg, 0.424 mmol) with 1a after 48 h gave 6a (91 mg, 76%)
after chromatography (petroleum ether/diethyl ether 6:1) as a colourless
oil. Rf =0.34; 1H NMR: d=0.85 (t, J=6.4 Hz, 3H; CH3), 1.18–1.40, (m,
16H; CH2 ꢃ8), 1.33 (t, J=7.2 Hz, 3H; OCH2CH3), 1.50–1.62 (m, 1H;
CH2C-5), 1.68–1.78 (m, 1H; CH2C-5), 2.81 (dd, J=8.6, 17.5 Hz, 1H; 4-
H), 3.20 (dd, J=10.9, 17.5 Hz, 1H; 4-H), 4.32 (q, J=7.2 Hz, 2H;
OCH2CH3), 4.71–4.80 ppm (m, 1H; 5-H); 13C NMR: d=14.0 (q, CH3),
14.1 (q, OCH2CH3), 22.6 (t, CH2), 25.0 (t, CH2), 29.2 (t, CH2), 29.3 (t,
CH2), 29.4 (t, CH2), 29.5 (t, 2C, CH2,), 31.8 (t, CH2), 35.0 (t, CH2C-5),
38.3, (t, C-4), 61.9 (t, OCH2CH3), 84.1, (d, C-5), 151.3 (s, C-3), 160.9 ppm
(s, C=O); IR (CDCl3): n˜ =2927 (s), 2855 (s), 1716 (s; C=O), 1588 (m; C=
N), 1466 (m), 1380 (m), 1256 cmÀ1 (s); MS (EI): m/z (%): 283 (2) [M]+,
266 (4), 254 (4) [MÀEt]+, 238 (2) [MÀOEt]+, 210 (26) [MÀCO2Et]+,
Reaction conditions affecting the condensation reaction of ethyl nitroace-
tate with allyl alcohol or styrene either neat or in water media: The con-
versions and spectroscopic yields reported in Table 2 refer to conditions
where eight reactions were carried out simultaneously. A mixture of
ethyl nitroacetate (1.06 mmol), allyl alcohol or styrene (0.424 mmol),
with base (0.0424 mmol) and water, buffer or HCl(aq) (1.4 mL) was pre-
pared in a sealed tube and left to react for the desired time period. The
reaction mixture was then extracted with CDCl3 (3ꢃ0.6 mL). 2,4-Di-
ACHTUNGTRENNUNGmethoxyacetophenone (14–21 mg, 0.078–0.12 mmol) was added as the in-
ternal standard and the 1H NMR spectrum recorded. Integration of the
3’-H and 5’-H proton signals of the internal standard (6.40–6.58, m) and
the signals of the 4-H protons of products from allyl alcohol and styrene
(3.16 ppm, m, and 3.20 ppm, dd, respectively) allowed the spectroscopic
yield to be calculated. Duplicate reactions were run if unclear results
were obtained.
142 (54) [MÀ
(CH2)9CH3]+, 116 (22), 43 (92), 41 (100); elemental analysis
ACHTUNGTRENNUNG
calcd (%) for C16H29NO3 (283.41): C 67.81, H 10.31, N 4.94; found: C
67.69, H 10.61 N 4.82.
Condensation reaction of allyl alcohol and styrene with ethyl nitroacetate
in water, with different amounts of NaOH (Figure 6): All reactions were
carried out in sealed tubes. Different volumes of aqueous 4.24m NaOH
(100, 75, 50, 25, 10, 5 mL) corresponding to a variable base/alkene molar
ratio (1.0, 0.75, 0.5, 0.25, 0.1, 0.05, respectively) were added to a mixture
of ethyl nitroacetate (1.06 mmol), allyl alcohol (0.424 mmol), or styrene
(0.424 mmol). Each mixture was then dissolved in a complementary
volume of heavy water (1.3, 1.325, 1.350, 1.375, 1.390, 1.395 mL, respec-
tively) to give an overall volume of 1.4 mL. Each mixture was vigorously
stirred at 608C. After 18 h each reaction mixture was concentrated, and
dissolved in CDCl3. Me2SO2 (14–20 mg) was added as the internal stan-
dard. The 1H NMR spectrum was then recorded and the spectroscopic
yield calculated as follows. Allyl alcohol: by integrating 4-H proton sig-
nals of the cycloadduct 2a (d=3.05–3.28 ppm, m, 2H) and the CH3
proton signal of the internal standard (d=2.57 ppm, s, 6H). Styrene: by
integrating 4-H proton signals of the cycloadduct 3a (d=3.2 ppm, dd,
1H) and the CH3 proton signal of the internal standard as above. No
conversion was seen without the addition of base. Duplicate reactions
were run if unclear results were obtained.
Condensation reaction of ethyl nitroacetate with 3-buten-1-ol to give
ethyl 5-(2-hydroethyl)-4,5-dihydro-3-isoxazolecarboxylate (4a): The reac-
tion of 3-buten-1-ol (30 mg, 0.416 mmol) with 1a after 16 h gave 4a
(66 mg, 84%) after chromatography (petroleum ether/diethyl ether 6:1,
then diethyl ether) as a colourless oil. Rf =0.41; elemental analysis calcd
(%) for C8H13NO4 (187.19): C 51.33, H 7.00, N 7.48; found: C 51.14, H
7.22, N 7.71. The spectral data are identical to those previously report-
ed.[28]
Condensation reaction of ethyl nitroacetate with 10-undecen-1-ol to give
ethyl 5-(2-hydroxynonyl)-4,5-dihydro-3-isoxazolecarboxylate (7a): The
reaction of 10-undecen-1-ol (72 mg, 0.423 mmol) with 1a after 72 h gave
unreacted alcohol (12 mg, Rf =0.64) and 7a (93 mg, 93% calculated
taking into account recovered 10-undecen-1-ol) after chromatography
(petroleum ether/ethyl acetate 4:1, then petroleum ether/ethyl acetate
1
3:1) as a white solid. Rf =0.18; m.p. 36–378C; H NMR: d=1.18–1.40 (m,
12H; CH2 ꢃ6), 1.34 (t, J=7.2 Hz, 3H; OCH2CH3), 1.50–1.62 (m, 3H;
CH2C-5, CH2CH2OH), 1.70–1.81 (m, 1H; CH2C-5), 2.81 (dd, J=8.8,
17.6 Hz, 1H; 4-H), 3.22 (dd, J=10.8, 17.6 Hz, 1H; 4-H), 3.62 (t, J=
6.8 Hz, CH2OH, 2H), 4.32 (q, J=7.2 Hz, 2H; OCH2CH3), 4.72–4.81 ppm
(m, 1H; 5-H); 13C NMR: d=14.1 (q, OCH2CH3), 25.1 (t, CH2), 25.7 (t,
CH2), 29.2 (t, CH2), 29.3 (t, 2C, CH2), 29.4 (t, CH2), 32.8 (t,
CH2CH2OH), 35.0, (t, CH2C-5), 38.4 (t, C-4), 62.0 (t, OCH2CH3), 63.1 (t,
CH2OH), 84.2, (d, C-5), 151.4 (s, C-3), 160.9 ppm (s, CO2Et); IR
Determination of ethyl nitroacetate solubilities in water and in the reac-
tion mixture: The solubility of 1a in water and in the reaction mixture at
room temperature and 608C were determined by measuring the integra-
1
tion values from the H NMR spectra as described above.
In water: (CH3)2SO2 (16.7 mg) as internal standard was dissolved in
heavy water (0.7 mL). This solution was saturated with ethyl nitroacetate
(1a) and the mixture was transferred to a septum-sealed 5 mm NMR
tube and placed in the probe of the spectrometer at 268C. The 1H NMR
spectra was recorded and the amount of dissolved 1a was calculated by
integrating the CH3 proton signal of the internal standard (d=3.16 ppm,
s, 6H) and the CH2O proton signal for 1a (d=4.22 ppm, q, 2H). The
concentration of 1a was calculated to be 0.17m.
(CDCl3): n˜ =2930 (s), 2856 (m), 1714ACTHNUGRTNEUNG(s; C=O), 1588 (w; C=N), 1256(m),
1127 cmÀ1 (w); MS (EI): m/z (%): 268 (<1) [MÀOH]+, 212 (4)
[MÀCO2Et]+, 182 (9), 142 (100) [MÀ
(CH2)9OH]+, 114 (27), 86 (12),
ACHTUNGTRENNUNG
81(12), 69 (24), 55 (44), 41 (48); elemental analysis calcd (%) for
C15H27NO4 (285.38): C 63.13, H 9.54, N 4.91; found: C 63.47, H 9.75, N
4.53.
Chem. Eur. J. 2012, 18, 2081 – 2093
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
2089

F. Machetti, F. De Sarlo et al.
Condensation reaction of ethyl nitroacetate with 2,2-dimethyl-4-pentenal
to give ethyl 5-(2,2-dimethyl-3-oxopropyl)-4,5-dihydro-3-isoxazolecarbox-
ylate (8a): The reaction of 2,2-dimethyl-4-pentenal (48 mg, 0.424 mmol)
with 1a after 42 h gave 8a (44–70 mg, 46–73%) after chromatography
(petroleum ether/ethyl acetate 4:1, then petroleum ether/ethyl acetate
3:1) as a yellowish oil. Rf =0.21; 1H NMR: d=1.10 (s, 3H; CCH3), 1.14
(s, 3H; CCH3), 1.32 (t, J=7.2 Hz, 3H; OCH2CH3), 1.73 (dd, J=3.6,
14.8 Hz, 1H; CH2C-5), 2.00 (t, J=9.2, 14.8 Hz, 1H; CH2C-5), 2.79 (dd,
J=8.0, 17.6 Hz, 1H; 4-H), 3.30 (dd, J=11.2, 17.6 Hz, 1H; 4-H), 4.32 (q,
J=7.2 Hz, 2H; OCH2CH3), 4.76–4.86 (m, 1H; 5-H), 9.44 ppm (s, 1H;
CHO); 13C NMR: d=14.0 (q, OCH2CH3), 21.4 (q, CCH3), 22.3 (q,
CCH3), 40.0, (t, C-4), 42.9 (t, CH2C-5), 44.8 (s, CCH3), 62.0 (t,
OCH2CH3), 80.6 (d, C-5), 151.5 (s, C-3), 160.6 (s, CO2Et), 204.6 ppm (d,
CHO); IR (CDCl3): n˜ =2981 (s), 2934 (s), 1724 (s; C=O), 1590 (m; C=
N), 1469 (m), 1380 (s), 1258 (s), 1129 cmÀ1 (s); MS (EI): m/z (%): 198
(12) [MÀCHO]+, 182 (34), 156 (100), 142 (74) [MÀCH2CH-
CO2Me), 174.1 ppm (s, CO2H); IR (KBr): n˜ =3000 (br; OH), 2957 (w),
1718 (s; C=O), 1591 (w; C=N), 1444 (m), 1260 cmÀ1 (m); MS (ESIÀ,
MeOH): m/z (%): 186 (100) [MÀ1]+; elemental analysis calcd (%) for
C7H9NO5 (187.15): C 44.92, H 4.85, N 7.48; found: C 44.90, H 4.55, N
7.49.
Condensation reaction of ethyl nitroacetate with 10-undecenoic acid to
give 9-(3-ethoxycarbonyl-4,5-dihydro-5-isoxazolyl)nonanoic acid (11a):
The reaction of 10-undecenoic acid (78 mg, 0.423 mmol) with 1a after
65 h gave 11a (105 mg, 83%) after chromatography (petroleum ether/
ethyl acetate 2:1) as a white powder. Rf =0.30; m.p. 59–638C; 1H NMR:
d=1.34 (t, J=7.2 Hz, 3H; CH3), 1.24–1.40 (m, 10H; CH2 ꢃ5), 1.50–1.64
(m, 3H; CH2C-5, CH2CH2CO2H), 1.69–1.80 (m, 1H; CH2C-5), 2.32 (t,
J=7.6 Hz, 2H; CH2CO2H), 2.81(dd, J=8.4, 17.6 Hz, 1H; 4-H), 3.22 (dd,
J=10.8, 17.6 Hz, 1H; 4-H), 4.32 (q, J=7.2 Hz, 2H; OCH2CH3), 4.71–
4.81 ppm (m, 1H; 5-H); 13C NMR: d=14.1 (q, CH3), 24.6 (t,
CH2CH2CO2H), 25.0 (t, CH2), 28.9 (t, CH2), 29.0 (t, CH2), 29.2 (t, 2 C,
CH2), 33.9 (t, CH2CO2H), 35.0 (t, CH2C-5), 38.4 (t, C-4), 62.0 (t,
OCH2CH3), 84.1 (d, C-5), 151.3 (s, C-3), 160.9 (s, CO2Et), 179.3 ppm (s,
CO2H); IR (CDCl3): n˜ =2932 (m), 2860 (w), 1713 (s; C=O), 1590 (w; C=
N), 1254 (m), 1129 cmÀ1 (m); MS (ESIÀ, MeOH): m/z (%): 298 (100)
[MÀ1]+; elemental analysis calcd (%) for C15H25NO5 (299.36): C 60.18,
H 8.42, N 4.68; found: C 60.36 , H 8.37, N 4.32.
ACHTUNGTRENNUNG
(CH3)2CHO]+, 128 (32), 114 (54), 85 (42), 72 (30); elemental analysis
calcd (%) for C11H17NO4 (227.26): C 58.14, H 7.54, N 6.16; found: C
57.74, H 7.84, N 6.09.
Condensation reaction of ethyl nitroacetate with 10-undecenal to give
ethyl 5-(3-oxononyl)-4,5-dihydro-3-isoxazolecarboxylate (9a): The reac-
tion of 10-undecenal (70 mg, 0.416 mmol) with 1a after 48 h gave 9a
(106 mg, 90%) after chromatography (petroleum ether/ethyl acetate 5:1,
then petroleum ether/ethyl acetate 4:1) as a colourless oil that became
yellowish on standing. Rf =0.23; 1H NMR: d=1.18–1.40 (m, 10H; CH2 ꢃ
5), 1.34 (t, J=7.2 Hz, 3H; OCH2CH3), 1.50–1.62 (m, 3H; CH2C-5,
CH2CH2CHO), 1.70–1.81 (m, 1H; CH2C-5), 2.40 (t, J=7.4 Hz, 2H;
CH2CHO), 2.80 (dd, J=8.0, 17.6 Hz, 1H; 4-H), 3.23 (dd, J=11.2,
17.6 Hz, 1H; 4-H), 4.32 (q, J=7.2 Hz, 2H; OCH2CH3), 4.68–4.86 (m,
1H; 5-H), 9.74 ppm (s, 1H; CHO); 13C NMR: d=14.1 (q, OCH2CH3),
22.0 (t, CH2CH2CHO), 25.0 (t, CH2), 29.1 (t, CH2), 29.2 (t, 2C, CH2),
29.5 (t, CH2), 35.0 (t, CH2C-5), 38.3 (t, C-4), 43.8 (t, CH2CHO), 62.0 (t,
OCH2CH3), 84.1, (d, C-5), 151.3 (s, C-3), 160.9 (s, CO2Et), 202.9 ppm (d,
CHO); IR (CDCl3): n˜ =2930 (s), 2857 (m), 1717 (s; C=O), 1590 (w),
1255 cmÀ1 (m); MS (EI): m/z (%): 282 (4) [MÀH]+, 254 (6) [MÀCHO]+,
Condensation reaction of ethyl nitroacetate with allylbenzene to give
ethyl 5-benzyl-4,5-dihydro-3-isoxazolecarboxylate (12a): The reaction of
allylbenzene (50 mg, 0.422 mmol) with 1a after 72 h gave 12a (62 mg,
62%) after chromatography (petroleum ether/ethyl acetate 5:1) as a col-
ourless oil. Rf =0.50; 1H NMR: d=1.34 (t, J=7.2 Hz, 3H; OCH2CH3),
2.88 (dd, J=6.8, 14.0 Hz, 1H; CH2C-5), 2.92 (dd, J=8.4, 17.8 Hz, 1H; 4-
H), 3.11 (dd, J=6.0, 14.0 Hz, 1H; CH2C-5), 3.18 (dd, J=10.8, 17.8 Hz,
1H; 4-H), 4.31 (q, J=7.2 Hz, 2H; OCH2CH3), 5.00–5.08 (m, 1H; 5-H),
7.19–7.28 (m, 3H; Ph-H), 7.28–7.35 ppm (m, 2H; Ph-H); 13C NMR: d=
14.1 (q, OCH2CH3), 37.8 (t, CH2C-5), 40.7, (t, C-4), 62.0 (t, OCH2CH3),
84.3, (d, C-5), 126.9 (d, C6H5-Cpara), 128.7 (d, 2 C, C6H5-C), 129.4 (d, 2 C,
C6H5-C), 135.9 (s, C6H5-Cipso), 151.4 (s, C-3), 160.7 ppm (s, C=O); IR
(CDCl3): n˜ =3023 (w), 2984 (w), 2930 (w), 1718 (s; C=O), 1589 (w; C=N),
1254 cmÀ1 (s); MS (EI): m/z (%): 142 (6) [MÀCH2C6H5]+, 91 (100)
[CH2Ph]+, 77 (7) [Ph]+, 65 (28); elemental analysis calcd (%) for
C13H15NO3 (233.26): C 66.94, H 6.48, N 6.00; found: C 66.97, H 6.57, N
6.02.
208 (4), 193 (8), 168 (9), 155 (80), 142 (100) [MÀ
(CH2)CHO]+, 114, (41).
ACHTUNGTRENNUNG
The 1H NMR spectra showed the presence of traces of hydrate 9a. Se-
lected signal: d=5.08–5.18 ppm (m, CH(OH)2).[65]
Condensation reaction of ethyl nitroacetate with 3-butenoic acid to give
(3-ethoxycarbonyl-4,5-dihydro-5-isoxazolyl)acetic acid (10a): 3-Butenoic
acid (42.5 mg, 0.494 mmol) with 1a was reacted together for 48 h. After
this time the reaction mixture was concentrated and the solid residue was
triturated and washed twice with diisopropyl ether (2ꢃ2 mL) to afford
the final product as a white powder. Alternatively the reaction mixture
was treated with water (10 mL), washed with hexane (3ꢃ5 mL) and care-
fully concentrated under reduced pressure. The solid residue was passed
through a short pad of silica gel (dichloromethane/MeOH 20:1) to afford
the acid 10a (80 mg, 81%) as a white solid. M.p. 111–1128C; 1H NMR:
d=1.35 (t, J=7.2 Hz, 3H; CH3), 2.68 (dd, J=7.2, 16.6 Hz, 1H;
CH2CO2H), 2.87 (dd, J=6.4, 16.6 Hz, 1H; CH2CO2H), 2.99 (dd, J=7.6,
18.0 Hz, 1H; 4-H), 3.40 (dd, J=10.8, 18.0 Hz, 1H; 4-H), 4.33 (q, J=
7.2 Hz, 2H; OCH2CH3), 5.10–5.20 ppm (m, 1H; 5-H); 13C NMR: d=14.1
(q, OCH2CH3), 38.8 (t, C-4), 39.0 (t, CH2CO2H), 62.2 (t, OCH2CH3), 79.0
(d, C-5), 151.6 (s, C-3), 160.4 (s, CO2Et), 173.9 ppm (s, CO2H); IR (KBr):
n˜ =2988 (w), 2929 (w) 1724 (s; C=O), 1705 (s; C=O), 1593 (w; C=N),
1258 cmÀ1 (m); MS (ESIÀ, MeOH): m/z (%): 200 (100) [MÀ1]+; elemen-
tal analysis calcd (%) for C8H11NO5 (201.18): C 47.76, H 5.51, N 6.96;
found: C 47.71 H 5.77, N 7.17.
Condensation reaction of ethyl nitroacetate with 2-allylphenol to give
ethyl 5-(2-hydroxybenzyl)-4,5-dihydro-3-isoxazolecarboxylate (13a): The
reaction of 2-prop-2-enylphenol (58 mg, 0.429 mmol) with 1a after 72 h
gave 13a (74 mg, 70%) after chromatography (petroleum ether/ethyl
1
acetate 5:1) as a colourless oil. Rf =0.23; H NMR: d=1.32 (t, J=7.2 Hz,
3H; OCH2CH3), 2.94–3.05 (m, 3H; CH2C-5 and 4-H), 3.19 (dd, J=10.8,
17.6 Hz, 1H; 4-H), 4.30 (q, J=7.2 Hz, 2H; OCH2CH3), 5.08–5.18 (m,
1H; 5-H), 5.84 (brs, OH, 1H), 6.77–6.90 (m, 2H; Ph-H), 7.05–7.16 ppm
(m, 2H; Ph-H); 13C NMR: d=14.0 (q, OCH2CH3), 35.5 (t, CH2C-5), 37.8,
(t, C-4), 62.1 (t, OCH2CH3), 84.0 (d, C-5), 116.3 (d, Ph-C), 120.9 (d, Ph-
C), 122.5 (s, Ph-C), 128.6 (d, Ph-C), 131.7 (d, Ph-C), 152.2 (s, C-3), 154.3
(s, Ph-COH), 160.6 ppm (s, C=O); IR (CDCl3): n˜ =3600 (m), 3560 (br),
1724 (s; C=O), 1590 (w), 1375 (m), 1256 cmÀ1 (s); MS (EI): m/z (%): 249
(4) [M]+, 232 (2), 204 (4), 142 (21) [MÀCH2C6H4OH]+, 131 (33), 107
(100), 91 (8) [CH2Ph]+, 77(32) [Ph]+; elemental analysis calcd (%) for
C13H15NO4 (249.26): C 62.64, H 6.07, N 5.62; found: C 61.85, H 6.03, N
5.30.
Condensation reaction of ethyl nitroacetate with butenylamine hydro-
chloride to give ethyl 5-(2-aminoethyl)-4,5-dihydro-3-isoxazolecarboxy-
late hydrochloride (14a): But-3-enylammonium chloride (46 mg,
0.424 mmol) was treated with 1a as described previously. After 42 h the
reaction mixture was diluted with water (5 mL) and washed with hexane
(3ꢃ5 mL) before purification by using Chromabond C8 (Macherey–
Nagel) column (water, then with 10% methanol in water). Concentration
of the eluant gave 14a (84 mg, 89%) as a semisolid residue. 1H NMR
(D2O): d=1.31 (t, J=7.2 Hz, 3H; OCH2CH3), 2.01–2.11 (m, 2H; CH2C-
5), 3.02 (dd, J=7.6, 18.0, 1H; 4-H), 3.15 (m, 2H; CH2NH2), 3.44 (dd, J=
10.8, 18.0, 1H; 4-H), 4.33 (q, J=7.2 Hz, 2H; OCH2CH3), 4.97–5.07 ppm
(m, 1H; 5-H); 13C NMR (D2O): d=13.8 (q, OCH2CH3), 32.5 (t, CH2C-5),
Condensation reaction of methyl nitroacetate with 3-butenoic acid to
give (3-methoxycarbonyl-4,5-dihydro-5-isoxazolyl)acetic acid (10b): 3-
Butenoic acid (39.3 mg, 0.456 mmol) was treated with 1b as described
previously. After 12 h the reaction mixture was diluted with water
(10 mL), and worked-up as described above to afford acid 10b (78 mg,
91%) as a white solid. M.p. 108–1098C; 1H NMR: d=2.68 (dd, J=7.2,
16.8 Hz, 1H; CH2CO2H), 2.87 (dd, J=6.4, 16.8 Hz, 1H; CH2CO2H), 3.00
(dd, J=8.0, 18.0 Hz, 1H; 4-H), 3.41 (dd, J=11.2, 18.0 Hz, 1H; 4-H), 3.87
(s, 3H; OCH3), 5.10–5.20 ppm (m, 1H; 5-H); 13C NMR: d=38.7 (t, C-4),
39.0 (t, CH2CO2H), 52.9 (q, OCH3), 79.1 (d, C-5), 151.3 (s, C-3), 160.8 (s,
2090
www.chemeurj.org
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2012, 18, 2081 – 2093

Isoxazolines and Isoxazolesf
FULL PAPER
36.9 (t, CH2NH3+), 38.8 (t, C-4), 63.8 (t, OCH2CH3), 82.5 (d, C-5), 154.0
(s, C-3), 162.1 ppm (s, CO2Me); IR (KBr): n˜ =2986 (s), 2933 (s), 1722 (s)
(C=O), 1598 (m; C=N), 1505 (m), 1262 cmÀ1 (s); MS (ESI+, MeOH): m/z
(%): 209 (6) [M+Na]+, 187 (100) [M+H]+; elemental analysis calcd (%)
for C8H14N2O3·HCl (222.67): C 43.16, H 6.79, N 12.58; found: C 43.56, H
6.40, N 12.28.
3H; OCH2CH3), 2.02–2.10 (m, 1H; CH2C-5), 2.22–2.32 (m, 1H; CH2C-
5), 2.86 (dd, J=7.6, 17.6 Hz, 1H; 4-H), 3.33 (dd, J=10.9, 17.6 Hz, 1H; 4-
H), 3.44–3.52 (m, 2H; CH2Br), 4.32 (q, J=7.0 Hz, 2H; OCH2CH3), 4.94–
5.30 ppm (m, 1H; 5-H); 13C NMR: d=14.1 (q, OCH2CH3), 28.2 (t,
CH2Br), 38.0 (t, CH2C-5), 38.5 (t, C-4), 62.1 (t, OCH2CH3), 81.4 (d, C-5),
151.5 (s, C-3), 160.5 ppm (s, CO2Et); IR (CDCl3): n˜ =2984 (m), 2939 (m),
1720 (s; C=O), 1590 (m; C=N), 1257 cmÀ1 (s); MS (EI): m/z (%): 251 (2)
[M+2]+, 249 (2) [M]+, 206 (5) [M+2ÀOEt]+, 204 (5) [MÀOEt]+, 143
Alternatively the reaction mixture was diluted with water (15 mL),
washed with diethyl ether (3ꢃ15 mL) and then the pH adjusted to about
10 by addition of aqueous NaOH (1m). This solution was extracted with
chloroform (3ꢃ15 mL) and the combined organic extracts were dried
with anhydrous Na2SO4, filtered and concentrated under reduced pres-
sure to afford the free amine conjugate base of 14a (28 mg, 35%) as a
(9), 142 (68) [MÀ
(CH2)2Br]+, 124 (10), 114 (12), 109 (8), 107 (8), 96 (16),
ACHTUNGTRENNUNG
88 (16), 70 (44), 42 (100); elemental analysis calcd (%) for C8H12NO3Br
(250.09): C 38.42, H 4.84, N 5.60; found: C 38.64, H 4.72, N 5.24.
Condensation reaction of methyl nitroacetate with ethyl allyl ether to
give 5-the methyl ester of ethoxymethyl-4,5-dihydro-isoxazole-3-carboxyl-
ic acid (18b): The reaction of 3-ethoxy-propene (36.5 mg, 0.424 mmol)
with 1b after 48 h gave 18b (36 mg, 46%) after chromatography (di-
chloromethane then dichloromethane/methanol 40:1) as a colourless oil.
Rf =0.57; 1H NMR: d=1.17 (t, J=6.8 Hz, 3H; OCH2CH3), 3.07–3.14 (m,
1H; 4-H), 3.17–3.24 (m, 1H; 4-H), 3.53 (q, J=6.8 Hz, 2H; OCH2CH3),
3.54–3.56 (m, 2H; CH2C-5), 3.86 (s, 3H; OCH3), 4.88–4.96 ppm (m, 1H;
5-H); 13C NMR: d=15.0 (q, OCH2CH3), 35.5 (t, C-4), 52.7 (q, OCH3),
67.2 (t, OCH2CH3), 70.8 (t, CH2C-5), 82.6 (d, C-5), 151.2 (s, C-3),
161.1 ppm (s, CO2Me); IR (CDCl3): n˜ =2978 (m), 2956 (m), 2931 (m),
2872 (m), 1724 (s; C=O), 1591 (w; C=N), 1444 (m), 1260 cmÀ1 (s); MS
(EI): m/z (%): 187 (<1), [M]+, 156 (2) [MÀOMe]+, 128 (14), 59 (100)
[CO2Me]+; elemental analysis calcd (%) for C8H13NO4 (187.19): C 51.33,
H 7.00, N 7.48; found: C 51.63 H 7.16, N 6.99.
1
colourless oil. H NMR: d=1.34 (t, J=7.1 Hz, 3H; OCH2CH3), 1.80–1.91
(m, 1H; CH2C-5), 1.92–2.03 (m, 1H; CH2C-5), 2.88 (dd, J=8.0, 17.6, 1H;
4-H), 3.33 (dd, J=10.8, 17.6, 1H; 4-H), 3.45–3.58 (m, 2H; CH2NH2), 4.33
(q, J=7.1 Hz, 2H; OCH2CH3), 4.85–4.95 ppm (m, 1H; 5-H); 13C NMR:
d=14.1 (q, OCH2CH3), 36.4 (t, CH2C-5), 38.7 (t, C-4), 39.3 (t, CH2NH2),
62.2 (t, OCH2), 80.4 (d, C-5), 151.5 (s, C-3), 160.5 ppm (s, CO2Et); IR
(CDCl3): n˜ =2983 (w), 2962 (w), 2928 (w), 1718 (s; C=O), 1590 (w; C=N),
1253 cmÀ1 (s).
Condensation reaction of methyl nitroacetate with butenylamine to give
methyl 5-(2-aminoethyl)-4,5-dihydro-3-isoxazolecarboxylate hydrochlo-
ride (14b): Aqueous NaOH (4.24m, 0.010 mL, 0.0424 mmol) was added
to a solution of 1b (62 mg, 0.518 mmol), but-3-enylammonium chloride
(22 mg, 0.207 mmol) and water (2.000 g) and the mixture vigorously
stirred in a sealed vessel at 608C. After 3 h the reaction mixture was
washed with hexane (3ꢃ5 mL) before purification by using a Chroma-
bond C8 (Macherey–Nagel) column (water, then with 10% methanol in
water). Evaporation of the eluant gave 14b (38 mg, 88%) as a semisolid
residue. 1H NMR (D2O): d=2.06–2.14 (m, 2H; CH2C-5), 3.06 (dd, J=
7.6, 18.0, 1H; 4-H), 3.19 (m, 2H; CH2NH2), 3.49 (dd, J=10.8, 18.0, 1H;
4-H), 3.91 (s, 3H; OCH3), 5.03–5.12 ppm (m, 1H; 5-H); 13C NMR (D2O):
d=32.5 (t, CH2C-5), 37.0 (t, CH2NH3+), 38.8 (t, C-4), 53.8 (q, OCH3),
82.6 (d, C-5), 153.8 (s, C-3), 162.6 ppm (s, CO2Me); IR (KBr): n˜ =3430
(br), 1729 (s; C=O), 1646 (m) 1599 (w; C=N), 1144 (w), 1259 cmÀ1 (m);
MS (ESI+, MeOH): m/z (%): 195 (14) [M+Na]+, 173 (100) [M+H]+; el-
emental analysis calcd (%) for C7H12N2O3·HCl (208.64): C 40.30, H 6.28,
N 13.43; found: C 34.82, H 5.21, N 11.49.
Condensation reaction of ethyl nitroacetate with allyl methyl sulfide to
give thyl 5-[(methylsulfanyl)methyl]-4,5-dihydro-3-isoxazolecarboxylate
(19a): Allyl methyl sulfide (37 mg, 0.424 mmol) was treated with 1a as
described previously. After 16 h the reaction mixture was concentrated,
the residue dissolved in diethyl ether (15 mL) and washed with brine (3ꢃ
15 mL), saturated aqueous Na2CO3 (3ꢃ15 mL), and brine again (3ꢃ
15 mL). The organic layer was dried with sodium sulphate and concen-
trated to afford 19a (46 mg, 53%) as a colourless oil. 1H NMR: d=1.33
(t, J=7.0 Hz, 3H; OCH2CH3), 2.16 (s, 3H; SCH3), 2.67 (dd, J=7.2,
14.0 Hz, 1H; CH2S), 2.77 (dd, J=4.8, 14.0 Hz, 1H; CH2S), 3.10 (dd, J=
7.6, 18.0 Hz, 1H; 4-H), 3.28 (dd, J=11.2, 18.0 Hz, 1H; 4-H), 4.31 (q, J=
7.0 Hz, 2H; OCH2CH3), 4.93–5.20 ppm (m, 1H; 5-H); 13C NMR: d=14.1
(q, OCH2CH3), 16.3 (q, SCH3), 37.7 (t, CH2S), 38.1 (t, C-4), 62.1 (t,
OCH2CH3), 83.0 (d, C-5), 151.4 (s, C-3), 160.5 ppm (s, CO2Et); IR
(CDCl3): n˜ =2984 (m), 2922 (m), 1716 (s; C=O), 1591 (m; C=N),
1260 cmÀ1 (s); MS (EI): m/z (%)=203 (<1), [M]+, 158 (2) [MÀOEt]+,
142 (10) [MÀMeSCH2]+, 114(1), 62 (35), 61 (100) [MeSCH2]+; elemental
Condensation reaction of ethyl nitroacetate with 5-nitro-1-pentene to
give ethyl 5-(3-nitropropyl)-4,5-dihydro-3-isoxazolecarboxylate (15a):
The reaction of 5-nitro-pent-1-ene (48.8 mg, 0.424 mmol) with 1a after
18 h gave 15a (93 mg, 95%) after chromatography (petroleum ether/di-
ethyl ether 1:1) as a colourless oil. The spectral data are identical to
those previously reported.[28] Rf =0.25; elemental analysis calcd (%) for
C9H14N2O5 (230.22): C 46.95, H 6.13, N 12.17; found: C 46.65, H 5.90, N
12.24.
analysis calcd (%) for C8H13NO3S
found: C 47.58, H 6.85, N 6.69.
ACHTUNGTRNE(NUNG 203.26): C 47.27, H 6.45, N 6.89;
Condensation reaction of ethyl nitroacetate with 5-hexenenitrile to give
5-(4,5-dihydro-5-isoxazolyl)butanenitrile (20a): The reaction of 5-hexene-
nitrile (40 mg, 0.424 mmol) with 1a after 16 h gave 20a (89 mg, 99%)
after chromatography (petroleum ether/ethyl acetate 5:1 then petroleum
Condensation reaction of ethyl nitroacetate with 5-hexen-2-one to give
ethyl 5-(3-oxobutyl)-4,5-dihydro-3-isoxazolecarboxylate (16a): The reac-
tion of 5-Hexen-2-one (42 mg, 0.424 mmol) with 1a after 72 h gave 16a
(85 mg, 94%) after chromatography (petroleum ether/ethyl acetate 5:1)
1
as
a
colourless oil. Rf =0.12; 1H NMR: d=1.33 (t, J=7.2 Hz, 3H;
ether/ethyl acetate 3:1) as a colourless oil. Rf =0.15; H NMR: d=1.33 (t,
J=7.0 Hz, 3H; OCH2CH3), 1.70–1.90 (m, 4H; 2ꢃCH2), 2.34–2.46 (m,
2H; CH2CN), 2.83 (dd, J=8.0, 17.6 Hz, 1H; 4-H), 3.28 (dd, J=11.2,
17.6 Hz, 1H; 4-H), 4.31 (q, J=7.0 Hz, 2H; OCH2CH3), 4.74–4.84 ppm
(m, 1H; 5-H); 13C NMR: d=14.0 (q, OCH2CH3), 16.9 (t, CH2CN), 21.4
(t, CH2), 33.9 (t, CH2C-5), 38.6 (t, C-4), 62.1 (t, OCH2CH3), 82.6 (d, C-5),
119.0 (s, CN), 151.4 (s, C-3), 160.5 ppm (s, CO2Et); IR (neat): n˜ =2983
OCH2CH3), 1.78–1.98 (m, 2H; CH2C-5), 2.14 (s, 3H; COCH3), 2.60 (t,
J=7.2 Hz, 2H; CH2CO), 2.81 (dd, J=8.0, 17.6 Hz, 1H; 4-H), 3.25 (dd,
J=10.8, 17.6, 1H; 4-H), 4.31 (q, J=7.2 Hz, 2H; OCH2CH3), 4.75–
4.84 ppm (m, 1H; 5-H);[66] 13C NMR: d=14.1 (q, OCH2CH3), 28.9 (t,
CH2C-5), 30.0 (q, COCH3), 38.6 (t, CH2CO), 38.7 (t, C-4), 62.0 (t,
OCH2), 82.6 (d, C-5), 151.5 (s, C-3), 160.6 (s, CO2Et), 207.4 ppm (s,
COCH3); IR (CDCl3): n˜ =2983 (m), 2939 (m), 1736 (s; C=O), 1716 (s;
C=O), 1589 (w; C=N), 1256 cmÀ1 (s); MS (EI): m/z (%): 170 (2)
[MÀCOMe]+, 168 (2), 156 (2), 155 (16), 142 (10), 140 (10) [MÀ
ꢀ
(s), 2939 (s), 2244 (m; C N), 1716 (s; C=O), 1589 (m, C=N), 1295 (s),
1127 cmÀ1 (s); MS (EI): m/z (%): 211 (3) [M+1]+, 165 (10), 142 (48)
[MÀ
(CH2)2CN]+, 114 (38), 96 (18), 41 (100); elemental analysis calcd
ACHTUNGTRENNUNG
(%) for C10H14N2O3 (210.23): C 57.13, H 6.71, N 13.33; found: C 56.80, H
6.89, N 12.92.
ACHTUNGTRENNUNG
(CH2)2COMe]+, 114 (35), 99 (60), 71 (100) [(CH2)2COMe]+; elemental
analysis calcd (%) for C10H15NO4 (213.23): C 56.33, H 7.09, N 6.57;
found: C 56.04, H 7.22, N 6.78.
Condensation reaction of ethyl nitroacetate with propargyl alcohol to
give the ethyl ester of 5-hydroxymethylisoxazole-3-carboxylic acid (21a):
The reaction of propargyl alcohol (23.7 mg, 0.424 mmol) with 1a after
48 h gave 21a (56.3 mg, 77%) after chromatography (dichloromethane
then dichloromethane/methanol 50:1) as a colourless oil. The spectral
data are identical to those previously reported.[28] Rf =0.22; elemental
Condensation reaction of ethyl nitroacetate with 4-bromobut-1-ene to
give ethyl 5-(2-bromoethyl)-4,5-dihydro-3-isoxazolecarboxylate (17a):
The reaction of 4-bromobut-1-ene (57 mg, 0.424 mmol) with 1a after 72 h
gave 17a (79 mg, 74%) after chromatography (petroleum ether/ethyl
1
acetate 6:1) as a colourless oil. Rf =0.17; H NMR: d=1.34 (t, J=7.0 Hz,
Chem. Eur. J. 2012, 18, 2081 – 2093
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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2091

F. Machetti, F. De Sarlo et al.
analysis calcd (%) for C7H9NO4 (171.15): C 49.12, H 5.30, N 8.18; found:
C 48.75, H 4.91, N 8.10.
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Acknowledgements
The authors thank the Ministero dell’Istruzione, Universitꢀ e Ricerca
(MIUR, Italy project COFIN 2008—prot. 200859234J) for financial sup-
port. E.T. and C.V. thank Ente Cassa di Risparmio di Firenze for a doc-
toral fellowship. B. Innocenti and M. Passaponti (Universitꢀ di Firenze)
are acknowledged for their technical support.
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[59] The Merck Index, 13th ed., Merck Manuals, Whitehouse Station,
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[60] The Merck Index, 13th ed., Merck Manuals, Whitehouse Station,
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[61] The Merck Index, 13th ed., Merck Manuals, Whitehouse Station,
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[35] Dehydration/condensation reactions in water are an intriguing chal-
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[41] This experiment is in agreement with our previous results: We
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[66] 1H NMR for this compound was previously reported with signifi-
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Received: October 4, 2011
Published online: January 10, 2012
Chem. Eur. J. 2012, 18, 2081 – 2093
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
2093