Conjugate addition versus cycloaddition/condensation of nitro compounds in water: Selectivity, acid-base catalysis, and induction period

Article abstract of DOI:10.1002/chem.201202698

Nitroacetates and nitroacetamides react in water as in chloroform with electron-deficient dipolarophiles to give condensation or conjugate addition products under base catalysis. In general, high selectivity towards condensation is observed in water, with

Full text of DOI:10.1002/chem.201202698

FULL PAPER
DOI: 10.1002/chem.201202698
Conjugate Addition versus Cycloaddition/Condensation of Nitro Compounds
in Water: Selectivity, Acid–Base Catalysis, and Induction Period
Luca Guideri,[a] Francesco De Sarlo,*[b] and Fabrizio Machetti*[a]
Abstract: Nitroacetates and nitroaceta-
mides react in water as in chloroform
with electron-deficient dipolarophiles
to give condensation or conjugate addi-
tion products under base catalysis. In
general, high selectivity towards con-
densation is observed in water, with
shorter induction periods than in
chloroform. In water, condensations
slowly occur even without base; kinetic
profiles evidence the catalytic effect of
the base, which should be related to
the conversion into the tautomer ni-
tronic acid. Condensations in water
provide convenient access to isoxazole
derivatives bearing various functional
groups including ammonium, carboxy,
and carboxyamide.
Keywords: cycloaddition · homoge-
neous catalysis · Michael addition ·
nitrogen heterocycles · water
Introduction
Nitro compounds are a useful source of carbon nucleo-
philes; the corresponding nitronate anions[1] react with elec-
tron-poor alkenes or alkynes (Michael acceptors)[2] and the
resulting conjugate addition has been extensively employed
for the formation of carbon–carbon bonds.[3] An ultimate
goal is to perform the reaction in water with an efficient cat-
alyst.[4]
On the other hand, activated primary nitro compounds
have been shown to undergo base-catalyzed condensations
with unsaturated substrates (dipolarophiles) to give isoxa-
zole derivatives [Equation (1)]. When these reactions are
carried out in chloroform, a certain specificity of the base is
observed; the best results, obtained in general with biprotic
In reactions of ethyl nitroacetate (1) in chloroform solu-
tion with dipolarophiles that are Michael acceptors, conden-
sations [Eq. (2)] compete, as expected, with the conjugate
addition [Eq. (3)]. The ratio between the two products (vari-
able during the reaction) was found to depend on the base
employed and on its concentration. The results were ration-
alized by considering that condensations to isoxazolines
occur after considerable induction times. Condensations, in
general, predominate when a CuII salt is added to the cata-
lytic system.[7]
Water as a reaction medium is known to dramatically
modify reaction selectivity and rate in comparison to the
same reaction performed in organic solvents.[8–10] This was
the case for condensations in water between nitroacetates
and dipolarophiles, in which a drop in the induction time
and rate enhancement in comparison with those observed
with chloroform solvent were evidenced. Under these condi-
tions no specificity of the base was observed; any organic or
inorganic base, at the appropriate concentration, had the
same effect provided its strength was higher than or compa-
rable to that of the nitronate (see below).[11]
tertiary
amines
{e.g.,
1,4-diazabicycloACTHNGUTERNNU[G 2.2.2]octane
(DABCO)}, have been related to their ability to establish
hydrogen bonds.[5,6]
[a] Dr. L. Guideri, Prof. Dr. F. Machetti
Istituto di Chimica dei Composti Organometallici
del Consiglio Nazionale delle Ricerche
c/o Dipartimento di Chimica ꢀUgo Schiff’
Universitꢁ di Firenze
Via della Lastruccia 13
50019 Sesto Fiorentino, Firenze (Italy)
Fax : (+39)0554573531
E-mail: fabrizio.machetti@unifi.it
fabrizio.machetti@cnr.it
[b] Prof. F. De Sarlo
Dipartimento di Chimica ꢀUgo Schiff’
Universitꢁ di Firenze
Via della Lastruccia 13
50019 Sesto Fiorentino, Firenze (Italy)
Fax : (+39)0554573531
E-mail: francesco.desarlo@unifi.it
In the present study we wish to examine how selectivity
and rates are modified in water compared with chloroform
and to gain insight into the mechanism of condensations in
water. To this end, kinetic profiles of several reactions either
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201203288.
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ꢂ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
665

Table 1. Effect of solvent and temperature on the competition between
in chloroform or in water are compared, with or without
base catalysis. We thus attempt to address the question con-
cerning the formation of nitrile oxide[12] as intermediates in
this condensation, or, in other words, determine whether de-
hydration precedes or follows cycloaddition.[13] Induction pe-
riods,[14,15] a common feature of these reactions, are often
observed in multistep reactions,[16] therefore, observed
changes might be related to changes in reaction mechanism.
Moreover, the selectivity observed in chloroform between
condensation and conjugate addition with dipolarophiles
that are Michael acceptors might be modified when the
same reactions are carried out in water.
adducts 3 and condensed cycloadducts 4.[a]
Entry
2
Base[b]
T
t
Conv. Solvent Yield 3 Yield 4
[8C] [h]
[%][c]
[%][d]
[%][d]
1[e]
2
a
a
a
a
b
b
b
b
b
c
c
c
c
c
c
c
d
d
d
d
d
d
e
e
e
f
DABCO
NaOH
NaOH
NaOH
DABCO
DABCO
NaOH
None
60
10
30
60
60
60
60
60
60
30
60
10
30
60
100
60
60
10
30
60
100
60
60
60
60
60
60
48 100
CHCl3
H2O
H2O
H2O
CHCl3
H2O
H2O
H2O
H2O
CHCl3
CHCl3
H2O
H2O
H2O
H2O
H2O
CHCl3
H2O
H2O
H2O
H2O
H2O
CHCl3
H2O
H2O
CHCl3
H2O
59
42
31
23
18
0
0
0
0
64
41
19
4
20
11
5
80
10
84
91
42
4
97
53
69
20
0
41
0
168
41
3[f]
4[f]
5[e]
6
168 100
20 100
48 100
20 100
20 100
19
21
82
90
95
34[g]
58[g]
36
36
0
26
52
37
34
19
0
0
6
29
24
0
0
6
0
50
Results and Discussion
7
8
9
20
53
None
72 100
240 100
The previously reported reactions in chloroform have been
repeated in water under similar conditions; the results are
collected in Table 1, together with those in chloroform,
which are included for comparison.[7]
10[e]
11[e]
12
13
14
15
16
17[e]
18
19
20
21
22
23[e]
24
25
26[h]
27
DABCO
DABCO
NaOH
NaOH
NaOH
NaOH
DABCO
DABCO
NaOH
NaOH
NaOH
NaOH
None
168
168
168
86
25
97
20 100
The occurrence of reactions in water, even without added
base, previously reported for allyl alcohol and styrene, is ex-
tended to electron-poor dipolarophiles (Table 1, entries 8, 9,
22, and 25).[11] Conjugate additions without base catalysis
are well known,[17] whereas condensations are new. More-
over, in the absence of base, condensations predominate
over additions, with the exception of vinyl ketone 2e; in this
case, the minor condensation product 4e is detectable. It
should be noted that no condensations are observed in
chloroform without base addition.[18]
Among the examples given in Table 1, high selectivity was
observed towards condensation only with dimethylacryla-
mide in water rather than in chloroform (2b; Table 1, en-
tries 5–7). In contrast, addition selectively occurs in the reac-
tion with ketone 2e in chloroform (Table 1, entry 23). The
products of condensations with methyl acrylate (Table 1, en-
tries 1–4), with acrylonitrile (Table 1, entries 10–16) and
with phenyl vinyl sulfone (Table 1, entries 17–22) occur as
mixtures with the respective addition products. Experiments
conducted over a range of temperatures confirmed that con-
5
20
68
93
20 100
168
168
26
88
20 100
5
72
72
33
DABCO
NaOH
none
DABCO
NaOH
48 100
21 100
20 100
48
20
f
20 100
[a] See the Experimental Section for details. [b] DABCO:
1,4-diazabicyclo[2.2.2]octane. [c] Conversion based on the consumption
AHCTUNGTRENNUNG
1
of dipolarophile determined by H NMR spectroscopic analysis. [d] Spec-
troscopic yield determined by 1H NMR spectroscopic analysis with the
use of an internal standard. [e] From ref. [7]. [f] Spectroscopic yields are
lower than conversions as a result of partial methyl ester hydrolysis.
[g] Partial hydrolysis of the ethyl ester was observed. [h] Compound 3 f
was isolated and characterized, see the Experimental Section.
densations are favored as the temperature increases
(Table 1, cf. entries 2–4, 12–14, and 19–20).[7]
Abstract in Italian: Nitroacetati e nitroacetammidi reagisco-
no in acqua o cloroformio con dipolarofili elettronpoveri per
dare prodotti di cicloaddizione-condensazione o di addizione
coniugata. La reazione ꢀ catalizzata da basi. In generale la
condensazione avviene con un’elevata selettivitꢁ in acqua,
con periodi di induzione piꢂ brevi rispetto al cloroformio. La
condensazione in acqua avviene, seppur in maniera piꢂ lenta,
anche in assenza di base. I profili cinetici evidenziano l’effet-
to catalitico della base che ꢀ stato correlato all’equilibrio di
tautomerizzazione del nitrocomposto nel corrispondente
acido nitronico. La condensazione in acqua ꢀ un’utile e con-
veniente procedura sintetica per la preparazione di derivati
isossazolici contenenti vari gruppi funzionali tra cui ammo-
nio, carbossilico, carbossiammide.
The ester groups undergo slow hydrolysis, particularly
when they are on the isoxazoline ring and for long reaction
times. The yields of products 4 are therefore severely re-
duced in some cases (Table 1, entries 4, 8, and 9), whereas
amides are less liable to this drawback. Reactions with
acrylic acid (2 f), also included in Table 1, show sluggish con-
version into the addition product (3 f) in chloroform
(Table 1, entry 26), whereas in water (Table 1, entry 27) se-
lective condensation to the isoxazoline 4 f was observed.
Chloroform, the standard solvent used in previously re-
ported reactions, contains about 90 ppm water. The model
reaction between ethyl nitroacetate (1) and dimethylacryla-
mide (2b) was repeated in chloroform saturated with water
(containing ca. 800 ppm of water). The results obtained in
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Aqueous Reactions of Nitro Compounds
FULL PAPER
the two cases do not differ significantly, the final proportion
being about 84% condensation to 4b versus 16% addition
to 3b in either reaction. As reported before,[11] condensa-
tions exhibit a dramatic shortening of induction times in
water compared with chloroform. To compare the kinetic
profiles in water and in chloroform, model reactions (methyl
nitroacetate with amides) were selected on the basis of com-
plete solubility in either deuterated solvents for direct NMR
monitoring.
Methyl nitroacetate (5) in chloroform undergoes conju-
gate addition with acrylamide (2g) after a long induction
time (Figure 1, some condensation product being detected
Figure 2. Kinetic profile for reactions between methyl nitroacetate (5)
and methacrylamide (8g) catalyzed by DABCO in water or chloroform.
!
Effect of solvent on the conversion of the dipolarophile: D2O ( ),
&
CDCl3 ( ). The reaction was performed in a septum-sealed NMR tube in
the probe of the spectrometer at 608C: methyl nitroacetate (0.265m),
methacrylamide (0.106m), and DABCO (0.0106m). See the Experimental
Section for details.
Figure 2 are repeated using the ethyl ester, as incomplete
solubility does not hamper the success of the reaction. Sev-
eral other reagents have limited solubility in water, particu-
larly phenylvinylsulfone (2d) and N-butyl nitroacetamide
(11), nevertheless, the condensations are successful.[11,19]
Therefore, the method appears to be of general preparative
value, using inexpensive catalyst and a straightforward pro-
cedure to deliver good to excellent yields. Examples of the
reaction performed on a larger scale (products 14g and 15g)
are described in the Experimental Section.
Reaction times up to 24 h are indicated for convenience
even though the dipolarophile was used up after a few hours
in many cases; only the 5-substituted 4,5-dihydroisoxazoles
(4 and 13; Table 2) were observed by 1H NMR spectroscopic
analysis of crude reaction mixtures, with negligible amounts
of by-products. Similarly, condensations with methacrylic
acid or its ester or amide selectively give the 5-disubstituted
regioisomers (14–17; Table 3).
Figure 1. Kinetic profile for reactions between methyl nitroacetate (5)
and acrylamide (2g) catalyzed by DABCO in water or chloroform.
~
Effect of solvent on the conversion of the dipolarophile: D2O ( 6),
&
CDCl3 (& 7 and
6). The reaction was performed in a septum-sealed
NMR tube in the probe of the spectrometer at 608C: methyl nitroacetate
(0.265m), acrylamide (0.106m), and DABCO (0.0106m). See the Experi-
mental Section for details.
later), whereas use of methacrylamide (8g) in the same
solvent gave only the condensation product (Figure 2). How-
ever, after short induction times in water both reactions go
to completion within 3 h to selectively give the condensation
products 6 (Figure 1) and 9 (Figure 2), respectively. It
should be noted that the two reaction profiles are almost
identical. As already pointed out,[11] no significant depend-
ence on the kind of base employed was observed in water
(Table 1, entries 6 vs. 7 and 14 vs. 16).
From condensations of methyl nitroacetamide with
methyl propiolate and with propiolic acid, minor amounts
(20a) or traces (20 f) of the 3,4-disubstituted regioisomers
were obtained in addition to the 3,5-disubstituted regioisom-
ers (Table 4).
Dipolarophiles bearing a carboxyl group have been em-
ployed in the past to directly prepare isoxazole derivatives
by cycloaddition with nitrile oxides.[20] However, reactions of
nitro compounds with carboxylic dipolarophiles such as 2 f
(Table 2, entries 2, and 9), 8 f (Table 2, entries 2, and 5), or
18 f (Table 4, entry 2) are reported here for the first time be-
cause the dehydrating agents previously used would interact
Useful preparations: Several reactions that selectively afford
condensation products in water, reported hereinafter, in-
volve nitro compounds with ester, amide, or ammonium
functional groups and dipolarophiles with ester, amide,
phosphonate, carboxylic, cyano, ammonium, or sulfonyl
groups. The model reactions illustrated in Figure 1 and
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667

F. Machetti, F. De Sarlo et al.
Table 2. 4,5-Dihydroisoxazoles from nitro compounds and terminal ole-
fins.[a]
Table 4. Isoxazoles from nitro compounds and alkynes.[a]
Entry
Product
X
Yield [%][b,c]
1
2
19a and 20a
19 f and 20 f
CO2Me
CO2H
71 (8:1)
75[d]
[a] Reaction conditions: water, 608C, NaOH (10 mol%). [b] Yield of iso-
lated product. [c] Regioisomeric ratio given in parentheses. [d] Traces of
Entry
Product
R
X
Yield [%][b]
1
2
3
4
5
6
7
8
4b
4 f
4g
4h
OEt
OEt
OEt
OEt
CONMe2
CO2H
CONH2
72
60
84
94
62
79
78
87
76
77
99
94
20 f.
+
CONH
ACHTNUGTERN(NUGN CH2)2NH3
tamide 12 (Table 3, entry 8) deserves some comment (see
below).
4i
OEt
P(O)(OEt)2
ACHTUNGTRENNUNG
13b
13c
13d
13 f
13g
13h
13i
NHMe
NHMe
NHMe
NHMe
NHMe
NHMe
NHMe
CONMe2
CN
SO2Ph
CO2H
CONH2
Attempted condensations with 1,2-disubstituted ethylenic
esters (dimethyl maleate, dimethyl fumarate, methyl croto-
nate) did not show different selectivities in water compared
to chloroform.[7] However, the yields were significantly af-
fected by ester hydrolysis. Because condensation reactions
with carboxylic dipolarophiles in water are practical, reac-
tions have been carried out directly on fumaric, maleic, and
E-crotonic acids with ethyl nitroacetate and N-methyl nitro-
acetamide. Refining these preparative methods was beyond
the scope of the current study at this stage. As an example,
the condensation of N-methyl nitroacetamide (10) with fu-
maric acid (21)[21b,26] is reported in the experimental section;
the main product (trans-dicarboxylic acid 22, ca. 65%) con-
tains approximately 10% of the cis-isomer 23 and traces of
the decarboxylated product 13 f.[27]
9
10
11
12
+
CONH
ACHTNUGTERN(NUGN CH2)2NH3
P(O)(OEt)2
AHCTUNGTRENNUNG
[a] Reaction conditions: water, 608C, NaOH (10 mol%). [b] Yield of iso-
lated product.
Table 3. 4,5-Dihydroisoxazoles from nitro compounds and methacrylic
derivatives.[a]
Acid-base catalysis and induction period: As pointed out
above, condensations of nitroacetic ester 1 occur slowly
even without base catalysis. N-Methyl nitroacetamide (10)
behaves similarly, thus suggesting that this might be the rule,
at least for reactions that are not exceedingly slow. Some
condensations showing this behavior have been selected as
model reactions with the aim of investigating the role of
acid-base catalysis and the origin of induction time.
N-Methyl nitroacetamide (10) in aqueous solution without
base or dipolarophile was almost unaffected after 24 h.
Under the same reaction conditions, 10 reacted with acryla-
mide (2g) to give the expected dihydroisoxazole derivative
13g without added base; both reagents are quite soluble in
water, and the medium is weakly acidic due to the presence
of N-methyl nitroacetamide (10) in excess (the pKa of
N-methylnitroacetamide was evaluated by potentiometric ti-
tration[28] to be 5.46). The kinetic profile in D2O,[29] illustrat-
ed in Figure 3 (top), exhibits a very long induction time (15
to 20 h), then the condensation is complete within 26 h. The
same reaction, carried out with addition of 0.1 equiv of base
(Table 2, entry 10), followed the kinetic profile illustrated in
Figure 3 (bottom); after a much shorter induction time, a
constant rate was attained at approximately 60% reaction
progress and the condensation was complete after 105 min.
Entry[a]
Product
R
X
Yield [%][b]
1
2
3
4
5
6
7
8
14a
14 f
14g
15a
15 f
15g
16a
17g
OEt
OEt
OEt
NHMe
NHMe
NHMe
NHnBu
CO2Me
CO2H
CONH2
CO2Me
CO2H
CONH2
CO2Me
CONH2
73
65
78
77
88
98
65
92
+
NHACHTUNRTGNE(UNG CH2)2NH3
[a] Reaction conditions: water, 608C, NaOH (10 mol%). [b] Yield of iso-
lated product.
with the carboxylic function. Syntheses from unsaturated
esters or nitriles are commonly reported, but require an ad-
ditional step to convert the adducts into carboxylic
acids.[21,22]
The above carboxylic acids are challenging substrates that
may interfere with the catalytic system (acrylic acid: pKa
[258C, H2O] 4.26,[23] propiolic acid: pKa [258C, H2O]
1.85[24,25]).
The presence of an ammonium ion in the dipolarophile
does not modify the reactivity (Table 2, entries 4 and 11),
nevertheless, the ammonium group as inner salt of nitroace-
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Aqueous Reactions of Nitro Compounds
FULL PAPER
Figure 4. Reaction profile of reactions of N-methyl nitroacetamide (10)
and acrylic acid (2 f) without addition of base (top) and with 0.1 equiv of
base (bottom). See the Experimental Section for details.
Figure 3. Reaction profile of reactions of N-methyl nitroacetamide (10)
and acrylamide (2g) without addition of base (top) and with 0.1 equiv of
base (bottom). See the Experimental Section for details.
Aqueous N-methyl nitroacetamide, under the same condi-
tions with base but without dipolarophile, decomposed
within 2 h into a mixture containing residual N-methyl nitro-
acetamide and N3,N5-dimethyl-3,4-bis-carbamoylfuroxan
(26; 15%) in addition to other unidentified products.
Any base, as already pointed out,[11] had the same catalyt-
ic effect provided its strength was higher or comparable to
that of the nitronate. However, the best results were ach-
ieved with 0.1 equiv of base. Increasing the proportion of
added base has been shown to reduce the condensation rate
in two model reactions of ethyl nitroacetate. After 18 h, no
condensation product was detected when 1 equiv of base
was added.[11]
ic acid (pKa 4.26,[23] 4.25[30]) and in Figure 5 (&) for propiolic
acid (pKa 1.85[24]). The usual pattern can be observed, with
long induction times and constant rates being observed
during the central part of the reactions. On addition of a
strong base (NaOH, 0.1 equiv), in fact this is converted into
weaker bases (nitronate and carboxylates) in amounts de-
pending on strength and concentration, and changing as the
reactions proceed.
In the reaction with acrylic acid, even in the presence of
the product 13 f (pKa 3.73, see the Experimental Section),
there was enough nitronate to ensure a considerable catalyt-
ic effect; the reaction profile of the catalyzed reaction is il-
lustrated in Figure 4 (bottom). However, in the presence of
acids much stronger than the nitronic acid, such as propiolic
acid and its condensation product, the isoxazole-5-carboxylic
acid derivative (pKa 2.04 is reported for the unsubstituted
No base was needed for N-methyl nitroacetamide (10) to
react with dipolarophiles containing a carboxylic function;
the kinetic profiles are illustrated in Figure 4 (top) for acryl-
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669

F. Machetti, F. De Sarlo et al.
Scheme 1. Reaction pathway via nitrile oxide.
competes with the condensation, as shown before, and the
addition products cannot be converted into isoxazoles.
The occurrence of condensations even without base catal-
ysis suggests that nitronic acid is the 1,3-dipole reacting with
dipolarophiles and the catalytic effect of a base should be
related to the equilibrium between nitro compound and ni-
tronic acid. In fact, tautomeric equilibria of nitro com-
pounds are known to be attained faster under base catalysis,
whereas acid catalysis does not seem actual.[33–36] A particu-
lar example of acid-catalyzed conversion into nitronic acid
was reported,[37,38] due to the presence of the tropylium ion
as an electrofuge instead of H+. It seems reasonable that a
sufficiently strong base is required to produce a catalytic
effect by substantially increasing the amount of nitronate.
In some cases (see Figure 4 and Figure 5), before the in-
duction period, a small amount of product (5–10%) was de-
tected. However, this does not seem to depend on the small
interval preceding reaction monitoring. On the other hand,
previous studies on the tautomerism of methyl nitroace-
tate[39,40] report a concentration of the nitronic acid tautomer
at equilibrium too low to be invoked as an explanation,
whereas, to the best of our knowledge, the tautomerism of
N-methyl nitroacetamide has not been investigated so far.[41]
The dramatic induction times observed in these reactions
are compatible with a multistep process, including tautome-
rization to nitronic acid,[42] cycloaddition, and dehydration,
as illustrated for N-methyl nitroacetamide in Scheme 2. The
induction period in consecutive reactions has been discussed
in detail[16] and shown to depend on relative rates of the
steps involved. The cycloaddition might be reversible or not,
whereas the final acid-catalyzed dehydration step occurs ir-
reversibly, possibly through the illustrated transition state.
Additional kinetic data would be required to identify the
rate-determining step. The reported experiments at different
temperatures indicate that condensations are favored by
temperature increases and this result would be consistent
with dehydration rather than cycloaddition as the rate-deter-
mining step.[43]
Figure 5. Reaction profile for the condensation of methyl nitroacetamide
&
(10) and propiolic acid (18 f) with base ( ) and without (&). N.B.,
1440 min = 1 day. See the Experimental Section for details.
isoxazole-5-carboxylic acid),[31] the amount of nitronate be-
comes negligible. In fact, the kinetic profile of the reaction,
&
illustrated in Figure 5 ( ), does not differ significantly from
that of the same reaction without base (&). These results, in-
dicating that the nitronate is the actual catalytic species, sug-
gest that tautomerization is the key step subject to basic cat-
alysis. However, because condensation is hampered by high
base concentrations (1 equiv),[11] nitronate is not the reacting
species in this reaction, unlike conjugate addition occurring
with dipolarophiles that are Michael acceptors.
On the other hand, when the nitro compound bears an
amino group, and therefore exists as an inner salt, this
slowly reacts with acrylamide to give addition rather than
condensation products. However, the corresponding hydro-
chloride reacted as usual upon addition of 0.1 equiv of base
(Table 3, entry 8). Constant reaction rates observed during
the central part of some reactions indicate that the steady-
state approximation appears to be effective in these cases.[32]
The above pieces of evidence provide some hints concern-
ing the mechanism. The observed stability of N-methyl ni-
troacetamide (10) in water and its almost quantitative con-
version (without base) into the condensation product with
acrylamide (2g) allows a path that operates through nitrile
oxide intermediate 25 in this case, to be ruled out
(Scheme 1). The presence of furoxan 26, detected in the ex-
periments in the presence of base, indicates that nitrile
oxide 25 might be an intermediate in a minor route in the
catalyzed condensation (Scheme 1). If the role of nitrile
oxide is negligible as an intermediate in this reaction, the
condensation should be reasonably ascribed to a 1,3-dipolar
cycloaddition preceding dehydration. In fact, a base-cata-
lyzed monopolar addition to electron-poor dipolarophiles
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Chem. Eur. J. 2013, 19, 665 – 677

Aqueous Reactions of Nitro Compounds
FULL PAPER
photometer; bands are characterized as broad (br), strong (s), medium
(m), or weak (w). Elemental analyses were obtained with an Elemental
Analyser Perkin–Elmer 240C apparatus. Water content of chloroform
was evaluated by Karl Fisher coulometric titration with a 831 KF Met-
rohm coulometer. The pH values were determined with a CyberScan510
pH meter produced by Eutech instruments. Solubility in water at 258C of
dipolarophiles (mol/dm3):[44] very soluble N,N-dimethylacrylamide (2b;
5.38), acrylonitrile (2c; 1.87 from literature[45]), acrylamide (2g; 30.3,
from literature at 308C[46]), soluble methacrylamide (8g; 0.27), methyl
acrylate (2a; 0.46), methyl methacrylate (8a; 0.25), acrylic acid (2 f;
0.55), methacrilic acid (8 f; 0.30), methyl vinylketone (2e; 0.58), diethylvi-
nylphosphonate (2i; 0.20), fumaric acid (21; 0.32 mol/L), slightly soluble:
phenylvinylsulfone (2d; 0.013). All compounds were named with Auton-
om (Beilstein Information Systems) and modified where appropriate.
Materials: All alkenes and alkynes are liquid at RT, except acryl amide
(2g; m.p. 84.5–85[47]), phenylvinylsulfone (2d; m. p. 70–718C[48]), and
methacrylamide (8g; m.p. 111.5–1128C[49]). Commercially available (Lan-
caster and Aldrich) ethyl nitroacetate (1), methylnitroacetate (5), organic
bases, olefins, and alkynes were used as supplied except acrylic acid,
which was purified by vacuum distillation before use. NaOH volumetric
standard 0.100 N water solution was supplied from Aldrich. CHCl3 (etha-
nol free) was filtered through a short pad of potassium carbonate just
before use and its water-content was determined to be 80–100 ppm.
Chloroform saturated with water contains 780 ppm of water. Water (de-
ionized) was twice distilled from KMnO4 before use. N-Methyl nitroacet-
amide (10) was prepared by following a previously reported procedure.[5b]
(2-Acryloylaminoethyl)carbamic acid tert-butyl ester was prepared by fol-
lowing a previously reported procedure.[50] Ambersept 900 anionic resin
was washed with deionized water until neutral pH before use.
Scheme 2. Plausible mechanism.
Conclusions
Reactions of nitroacetic esters or amides with electron-defi-
cient dipolarophiles in water selectively produce isoxazole
derivatives as a result of cycloaddition-condensation, where-
as in chloroform, CuII catalysis is required for the same pur-
pose. The method appears to be of preparative value, with
good to excellent yields and compatibility with many func-
tional groups. Slow condensations occur even without base
catalysis; long induction periods are ascribed to pre-equili-
bria that are followed by acid-catalyzed irreversible water
elimination.
Determination of ionization constants: The ionization constant of nitro
compound 10 was determined in water by potentiometric titration. The
procedure is described in the Supporting Information.
The pKa values in water for methyl nitroacetate (5) and 3-(methylcarba-
moyl)-4,5-dihydroisoxazole-5-carboxylic acid (13 f) were determined with
identical procedures. pKa (5) 5.68 (T=238C) (Lit. 5.56,[39] 5.82[51]); pKa
(13 f) 3.73 (T=228C).
Screening of reaction conditions (Table 1): The conversions and spectro-
scopic yields reported in Table 1 refer to reactions performed in an appa-
ratus in which eight reactions were carried out simultaneously. A mixture
of ethyl nitroacetate (1; 1.06 mmol), base (0.0424 mmol or none), and
olefin (0.424 mmol) in water or chloroform (1.4 mL) was kept at the indi-
cated temperature. For each dipolarophile, details of experiments are de-
scribed in the Supporting Information. Compound 3f (2-nitro-pentane-
dioic acid 1-ethyl ester) was prepared for reference as reported in the
Supporting Information. Spectroscopic data are in agreement with those
previously reported.[52]
Experimental Section
General methods: Melting points were determined in capillaries with a
Bꢃchi 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-
ized with UV light and/or by dipping the plates into a solution of per-
manganate followed by heating with a heat gun) carried out on alumina-
backed plates coated with 25 mm silica gel (Merck F254), with the same
eluant indicated for the column chromatography. For gradient column
chromatography Rf values refer to the more polar eluant. Solvent remov-
al was performed by evaporation on a rotavap at RT. 1H and 13C NMR
spectra were recorded with a Varian Mercuryplus 400 spectrometer (op-
erating at 400 MHz for 1H and 100.58 MHz for 13C) unless otherwise
stated. The 1H NMR data are reported as multiplicity (s=singlet, d=
doublet, t=triplet, m=multiplet or unresolved, br=broad signal), cou-
pling constant(s) in Hz, integration). Multiplicity of the 13C NMR signals
and assignments were determined by means of gHSQC and gHMBC ex-
periments. Chemical shifts were determined relative to the residual sol-
vent peak (CHCl3: d=7.24 ppm for 1H NMR and d=77.0 ppm for
Condensation of acrylamide (2g; Figure 1) and of methacrylamide (8g;
Figure 2) with methyl nitroacetate (5) in water: Reactions were run in a
septum-sealed 5 mm NMR tube spinning (20 Hz) in the probe of the
spectrophotometer at 608C for reaction times less than 24 h. For longer
experiments, reactions were run in a thermostated oil bath at 608C. See
the Supporting Information for details and spectroscopic data for com-
pounds 6, 7, and 9.
Kinetic profiles: General procedure for data reported in Figures 3–5 are
described in the Supporting Information.
Behavior of N-methyl nitroacetamide (10) in water in the absence of di-
polarophile:
a) Without added base: The 1H NMR spectrum of a solution of 10
(37.5 mg, 0.318 mmol) and CH3CN (10 mg) in D2O (0.755 g, 0.70 mL)
heated at 608C was registered after 10 min and after 24 h: no difference
was observed.
b) With added base: The 1H NMR spectrum of a solution of 10 (37.5 mg,
0.318 mmol), 4.24m NaOH (0.005 mL, 0.0212 mmol), and CH3CN
(10 mg) in D2O (0.750 g, 0.695 mL) heated at 608C was registered at in-
tervals of 10 min. After 2 h, the signals of furoxan 26 were observed in
addition to other unidentified signals. After 24 h, no residual signal of N-
methyl nitroacetamide (10) was detected.
1
13C NMR; H2O: d=4.79 ppm for H NMR). Chemical shifts for 13C NMR
in D2O are given relative to CH3CN (d=1.47 ppm) as internal reference.
EI (electron impact) mass spectra were obtained with
a Shimadzu
QP5050A quadrupole based mass spectrometer (direct introduction
unless otherwise stated, at ionizing voltage of 70 eV). Ion mass/charge
ratios (m/z) are reported as values in atomic mass units followed by the
intensities relative to the base peak in parenthesis. ESI (electronspray
ionization) mass spectra were obtained with a ThermoFisher LCQ-Fleet
ion trap instrument and spectra were registered with either ESI+ or ESIÀ
techniques. IR spectra were recorded with a Perkin–Elmer 881 spectro-
Chem. Eur. J. 2013, 19, 665 – 677
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671

F. Machetti, F. De Sarlo et al.
Compound 26: Data from crude reaction mixture evaporated to dryness.
1H NMR (400 MHz, CDCl3): d=3.02 (d, J=4.8 Hz, 3H; CH3NH), 3.04
(d, J=4.8 Hz, 3H; CH3NH), 8.62 (br s, 1H; NH), 9.60 ppm (br s, 1H;
NH);[53] 13C NMR (100.58 MHz, CDCl3): d=26.6 (q, 2 C; NHCH3), 110.1
(s, C=N+OÀ), 150. 5 (s, C=N), 155.6 (s, CO), 156.0 ppm (s, CO); MS
(ESI+): m/z: 201 [M + H]+.
1H NMR (400 MHz, D2O): d=3.22 (t, J=6.0 Hz, 2H; CH2NH3+), 3.62 (t,
J=5.2 Hz, 2H; CH2NHCO), 5.83 (dd, J=2.4, 9.2 Hz, 1H; CH<C= >
CH2), 6.23–6.28 (m, 1H; CH<C= >CH2), 6.29–6.35 ppm (m, 1H; CH<
C= >CH2); 13C NMR (100.59 MHz, D2O): d=37.4 (t, CH2NHCO), 39.8
(t, CH2NH3+), 117.0 (q, 1J
ACHTUNGTRENNUNG
>CH2), 130.2 (d, CH<C= >CH2), 163.6 (q, 2J
AHCTUNGTRENNUNG
170.0 ppm (s, CONH); IR (CDCl3): n˜ =3600–2400 (br), 1766 (w),
1667 cmÀ1 (m); MS (ESI+): m/z (%): 115 [M+H]+.
N-Butyl-2-nitroacetamide (11): A mixture of methyl nitroacetate (5;
0.33 g, 2.8 mmol) and N-butylamine (2.02 g, 28 mmol) was stirred at RT
for 2 days. After this time, excess amine was removed under reduced
pressure. The residue was cooled, acidified with 3 N HCl to pH 3–4 and
extracted with EtOAc (4ꢄ10 mL). The combined organic phases were
dried over Na2SO4, filtered, and concentrated under reduced pressure to
give 11 (0.440 g, 98%) as a low-melting solid.[54] 1H NMR (400 MHz,
CDCl3): d=0.91 (t, J=7.2 Hz, 3H; CH3), 1.28–1.40 (m, 2H;
CH2CH2CH3), 1.46–1.58 (m, 2H; CH2CH2CH3), 3.22–3.38 (m, 2H;
CH2NHCO), 5.06 (s, 2H; CH2NO2), 6.52 ppm (br s; NH); 13C NMR
(100.58 MHz, CDCl3): d=13.6 (q, CH3), 19.9 (t, CH2CH3), 31.1 (t,
CH2CH2CH3), 39.9 (t, CH2NHCO), 77.9 (t, CH2NO2), 159.9 ppm (s, CO);
IR (CHCl3): n˜ =3417 (w), 2962 (m), 2933 (m), 2873 (w), 1622 (s) (C=O),
1560 (s), 1533 (s), 1465 (w), 1377 cmÀ1 (w); MS (ESIÀ): m/z (%): 159
(MÀ1)À; elemental analysis calcd (%) for C6H12N2O3 (160.17): C 44.99,
H 7.55, N 17.49; found: C 44.96, H 7.84, N 17.69.
Preparation of isoxazolines (Table 2, Table 3) and isoxazoles (Table 4):
General procedure: Aqueous 4.24m NaOH (0.010 mL, 0.0424 mmol) was
added to a mixture of nitro compound (0.636 mmol, unless otherwise
stated) 1, 10, 11 or 12 with alkene or alkyne (0.424 mmol) and water
(1390 mg), and the mixture was vigorously stirred in a sealed tube at
608C. After the indicated time, the reaction mixture was worked-up and,
if necessary, the residue was purified by chromatography on silica gel
with the indicated eluant.
Ethyl
5-[(dimethylamino)carbonyl]-4,5-dihydroisoxazole-3-carboxylate
(4b): From N,N-dimethylacrylamide (2b; 42 mg, 0.424 mmol, 44 mL) and
ethyl nitroacetate (1; 85 mg, 0.636 mmol, 70 mL). After 20 h, the reaction
mixture was concentrated under reduced pressure and the residue was
purified by chromatography on silica gel (hexane/ethyl acetate, 1:1; Rf =
0.15) to give 4b (65 mg, 72%) as a colorless oil. Elemental analysis calcd
(%) for C9H14N2O4 (214.22): C 50.46, H 6.59, N 13.08; found: C 50.27, H
6.61, N 13.33. The spectral data are identical to those previously report-
ed.[7]
2-(2-Nitro-acetylamino)ethylammonium chloride (12·Cl): Prepared as
previously reported.[55] Ethylenediamine (0.673 mg, 11.2 mmol) was
added to a mixture of methyl nitroacetate (5; 1.33 g, 11.2 mmol), pyridine
(1.4 mL), water (1.4 mL), and the reaction mixture was stirred at 1008C.
After 45 min, the reaction mixture was cooled and concentrated under
reduced pressure. The residue was treated with MeOH and the precipi-
tate was filtered, washed with MeOH, and dried to give N-nitroacetyl-
1,2-ethylenediamine (1.1 g, 66%) as a yellowish solid; m.p. 140–1428C
(dec.) [Lit.[55] 140–1428C (dec.)]; 1H NMR (400 MHz, D2O): d=3.23 (t,
Compound 4 f: From acrylic acid (2 f; 30.6 mg, 0.424 mmol, 29.1 mL) and
ethyl nitroacetate (1; 85 mg, 0.636 mmol, 70 mL). After 20 h, the reaction
mixture was neutralized with aqueous 4m NaOH and washed with diethyl
ether (4ꢄ1.5 mL). The aqueous phase was acidified to pH 1 with aqueous
3m HCl and washed with hexane (2ꢄ2 mL) then extracted with ethyl
acetate (4ꢄ2 mL). The combined ethyl acetate phases were dried over
Na2SO4, filtered, and concentrated under reduced pressure to afford 4 f
(48 mg, 60%) as a colorless oil.[22] Alternatively, the reaction mixture was
carefully concentrated under reduced pressure and the residue was puri-
fied by chromatography on silica gel (elution first with CHCl3 and then
with CHCl3/iPrOH/AcOH, 9:1:0.1; Rf =0.36) to give 4 f as a colorless oil
J=5.9 Hz, 2H; CH2NH2), 3.66 (t, J=5.9 Hz, 2H; CH2CONH), 6.52 ppm
À
(s, 1H; CH=NO2
;
1H NMR (400 MHz, 608C, D2O): d=3.55 (t, J=
6.4 Hz, 2H; CH2NH2), 3.97 ppm (t, J=6.4 Hz, 2H; CH2CONH); CH=
À
NO2
not detected; 13C NMR (100.58 MHz, D2O): d=37.1 (t,
CH2CONH), 40.1 (t, CH2NH2), 166.9 ppm (s, CO), CH2NO2 not detect-
ed; elemental analysis calcd (%) for C4H9N3O3 (147.13): C 32.65, H 6.17,
N 28.56; found: C 32.23, H 6.47, N 28.85.
1
(yield as above). H NMR (400 MHz, CDCl3): d=1.37 (t, J=7.2 Hz, 3H;
CH2CH3), 3.52–3.53 (m, 1H; 4-H), 3.54–3.56 (m, 1H; 4-H), 4.36 (q, J=
1
The inner salt was dissolved in aqueous 5% HCl (pH 1) then dried to
give the chloride of 12 (1.37 g, 99%); m.p. 118–1218C (dec.); 1H NMR
(400 MHz, D2O): d=3.26 (t, J=18 Hz, 2H; CH2NH3+), 3.66 (t, J=
18 Hz, 2H; CH2CONH), 5.41 ppm (m, exchange with D2O, CH2NO2);
7.2 Hz, 2H; CH2CH3), 5.24 ppm (dd, J=8.6, 10.7 Hz, 1H; H-5); H NMR
(400 MHz, D2O): d=1.37 (t, J=7.2 Hz, 3H; CH2CH3), 3.52 (unsymmetri-
cal dd, J=7.2, 18.0 Hz, 1H; 4-H), 3.70 (unsymmetrical dd, J=12.8,
18.0 Hz, 1H; 4-H), 4.40 (q, J=7.2 Hz, 2H; CH2CH3), 5.40 ppm (dd, J=
7.2, 12.8 Hz, 1H; H-5); 13C NMR (100.58 MHz, CDCl3): d=14.0 (q,
CH3), 37.8 (t, C-4), 62.6 (t, CH2O), 79.1 (d, C-5), 151.2 (s, C-3), 159.7 (s,
CO2Et), 173.1 ppm (s, CO2H); IR (neat): n˜ =3400–2200 (broad signal),
2985 (m), 1730 (s), 1601 (w) (C=N), 1562 (w), 1257 cmÀ1 (m); MS (ESIÀ,
MeOH): m/z: 186 [MÀH]À; elemental analysis calcd (%) for C7H9NO5
(187.15): C 44.92, H 4.85, N 7.48; found: C 44.77, H 4.70, N 7.10.
+
13C NMR (100.58 MHz, D2O): d=37.8 (t, CH2CONH), 39.4 (t, CH2NH3
), 165.0 ppm (s, CO), CHNO2 not detected; IR (KBr): n˜ =3600–2400
(br), 1670 (s), 1578 (s), 1561 (s), 1494 (m), 1435 (w), 1385 (w), 1276 (w),
1176 cmÀ1 (w). MS (ESI+): m/z (%): 148 [M+H]+; elemental analysis
.
calcd (%) for C4H10N3O3 HCl (183.59): C 26.17, H 5.49, N 22.89; found:
C 26.26, H 5.63, N 22.75.
N-(2-Aminoethyl)acrylamide hydrochloride (2h·Cl): 2-Acryloylaminoe-
thylcarbamic acid tert-butyl ester (214 mg, 1 mmol) was dissolved in a
cooled solution of 3 N HCl (0.5 mL) and MeOH (1.5 mL). The mixture
was then stirred for 30 min at r.t., the solvent was removed under re-
duced pressure, and the residue was carefully triturated with diethyl
ether to afford 2h·Cl (148 mg, 99%) as a white powder; m.p. 79–818C
Ethyl 5-carbamoyl-4,5-dihydroisoxazole-3-carboxylate (4g): From acryla-
mide (2g; 30.1 mg, 0.424 mmol) and ethyl nitroacetate (1; 85 mg,
0.636 mmol, 70 mL). The reaction mixture was cooled after 6 h and kept
at 48C overnight. The liquid was removed and the precipitate was
washed with cold H2O (1 mL) and then warmed at 608C in an oven to
give 4g (52.7 mg) as a white powder. The aqueous fractions were com-
bined and evaporated to dryness. The residue was dissolved in CHCl3
and filtered through a short pad of silica gel. The solution was concen-
trated to afford additional 4g (13.3 mg) as a white powder. Overall yield
84%; m.p. 123–1248C;[56] 1H NMR (400 MHz, CDCl3): d=1.36 (t, J=
7.2 Hz, 3H; CH2CH3), 3.52 (d, J=4.4 Hz, 1H; 4-H), 3.54 (d, J=1.2 Hz,
1H; 4-H), 4.34 (q, J=7.2 Hz, 2H; CH2CH3), 5.17 (dd, J=7.6, 10.8 Hz,
1H; 5-H), 5.82 (br. s, 1H; NH), 6.58 ppm (br. s, 1H; NH); 13C NMR
(100.59 MHz, CDCl3): d=14.0 (q, CH3), 38.2 (t, C-4), 62.5 (t, CH2O),
80.4 (d, C-5), 152.2 (s, C-3), 159.5 (s, CO2Et), 172.1 ppm (s, CONH2); IR
(KBr): n˜ =3427 (m) (N-H), 3192 (m), 2987 (w), 1725 (s) (OC=O), 1654
(s) (NC=O), 1634 (m), 1605 (w) (C=N), 1423 (w), 1326 (w), 1264 cmÀ1
(m); MS (EI): m/z (%): 186 (3) [M]+, 142 (57) [MÀCONH2]+, 114 (14),
70 (33), 44 (100) [CONH2]+; elemental analysis calcd (%) for C7H10N2O4
(186.17): C 45.16; H 5.41; N 15.05; found: C 45.10; H 5.19; N 14.75.
1
(dec.); H NMR (400 MHz, D2O): d=3.24 (t, J=6.0 Hz, 2H; CH2NH3+),
3.63 (t, J=5.2 Hz, 2H; CH2NHCO), 5.84 (dd, J=2.0, 9.6 Hz, 1H; CH=
CH2), 6.23–6.28 (m, 1H; CH=CH2), 6.29–6.35 ppm (m, 1H; CH=CH2);
+
13C NMR (100.59 MHz, D2O): d=37.4 (t, CH2NHCO), 39.8 (t, CH2NH3
), 128.6 (t, CH=CH2), 130.1 (d, CH=CH2), 170.0 ppm (s, CONH); IR
(CDCl3): n˜ =3600–2400 cmÀ1 (br); MS (ESI+): m/z (%): 115 [M+H]+; el-
emental analysis calcd (%) for C5H10N2O·HCl (150.06): C 39.87, H 7.36,
N 18.60; found: C 39.93, H 7.43, N 19.02.
N-(2-Aminoethyl)acrylamide trifluoroacetic acid salt (2h trifluoroace-
tate): 2-Acryloylamino-ethyl-carbamic acid tert-butyl ester (214 mg,
1 mmol) was treated with trifluoroacetic acid (3 mL, 39 mmol) in CH2Cl2
(2 mL) at r.t. for 1 h. After this time, the solvent was removed under re-
duced pressure and the residue was carefully triturated with diethyl ether
to afford 2h trifluoroacetate (224 mg, 99%) as
a dark-yellow oil.
672
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Chem. Eur. J. 2013, 19, 665 – 677

Aqueous Reactions of Nitro Compounds
FULL PAPER
À
5-(2-Amino-ethylcarbamoyl)-4,5-dihydroisoxazole-3-carboxylic acid ethyl
ester trifluoroacetic salt (4h trifluoroacetate): From 2h trifluoroacetate
(97 mg, 0.424 mmol) and ethyl nitroacetate (1; 85 mg, 0.636 mmol,
70 mL). After 24 h, the mixture was diluted with H2O (5 mL) and washed
with CHCl3 (3ꢄ5 mL). The aqueous phase was evaporated under re-
duced pressure to give the product 4h trifluoroacetate (150 mg, 94%) as
a yellow oil. 1H NMR (400 MHz, D2O): d=1.36 (t, J=6.9 Hz, 3H;
CH2CH3), 3.21 (t, J=6.0 Hz, 2H; CH2NH3+), 3.50 (unsymmetrical dd,
J=6.8, 18.4 Hz, 1H, 4-H), 3.52–3.67 (m, 2H; CH2NCO), 3.69 (unsymmet-
rical dd, J=12.4, 18.4 Hz, 1H; 4-H), 4.35 (q, J=6.9 Hz, 2H; CH2CH3),
5.40 ppm (dd, J=6.8, 12.4 Hz, 1H; 5-H); 13C NMR (100.58 MHz, D2O):
d=13.8 (q, CH3), 37.4 (t, CH2NH3+), 38.4 (t, C-4), 39.6 (t, CH2NCO),
2945 (w) (C H), 2245 (w) (CꢀN), 1685 (s) (C=O), 1604 (w) (C=N),
1544 (m), 1418 (w), 1267 cmÀ1 (w); elemental analysis calcd (%) for
C6H7N3O2 (153.14): C 47.06, H 4.61, N 27.44; found: C 46.71, H 4.75, N
27.30.
4,5-Dihydro-N-methyl-5-(phenylsulfonyl)isoxazole-3-carboxamide (13d):
From phenylvinylsulfone (2d; 71.3 mg, 0.424 mmol) and N-methyl nitroa-
cetamide (10; 125.1 mg, 1.06 mmol). After 5 h, 13d began to precipitate
out of the solution as a fine white powder. After 22 h, the reaction mix-
ture was cooled and the white precipitate was collected by centrifugation,
washed with cold water (0.7 mL), and oven-dried at 508C to afford pure
13d (99 mg, 87%) as
a
white powder; m.p. 99–1018C; 1H NMR
(400 MHz, CDCl3): d=2.87 (d, J=4.8 Hz; NHCH3), 3.67 (unsymmetrical
dd, J=11.4, 19.6 Hz, 1H; 4-H), 3.93 (unsymmetrical dd, J=5.2, 19.6 Hz,
1H; 4-H), 5.50 (dd, J=5.2, 11.0 Hz, 1H; 5-H), 6.48 (br. s, 1H; NH), 7.56–
7.62 (m, 2H; Ph-H), 7.68–7.73 (m, 1H; Ph-H), 7.93–7.97 ppm (m, 2H;
Ph-H); 13C NMR (100.58 MHz, CDCl3): d=26.2 (q, NHCH3), 35.9 (t, C-
4), 93.9 (d, C-5), 129.4 (d, 2 C; Ph-Cortho), 129.7 (d, 2 C; Ph-C), 134.8 (d,
Ph-C), 135.0 (s, Ph-Cipso), 154.2 (s, C-3), 158.2 ppm (s, CONHMe); MS
(EI): m/z (%): 142 (25), 127 (20) [MÀSO2Ph]+, 77 (30) [C6H5]+, 70 (9),
58 (100) [CONHMe]+; IR (CDCl3): n˜ =3402 (s) (N-H), 3070 (w), 2980
(w), 1676 (s) (C=O), 1609 (m) (C=N), 1539 (m), 1447 (w), 1318 cmÀ1 (w);
elemental analysis calcd (%) for C11H12N2O4S (268.29): C 49.24, H 4.51,
N 10.44; found: C 48.846, H 4.334, N 10.81.
64.1 (t, CH2O), 81.3 (d, C-5), 117.0 (q, JACTHUNGTRENNUNG
2
(s, C-3), 161.4 (s, CO2Et), 163.6 (q, JACTHUNGTRENNNUG
(s, CONH); IR (MeOH): n˜ =1729 (s) (OC=O), 1680 (s) (NC=O), 1601
(w) (C=N), 1543 cmÀ1 (w); MS (ESI+): m/z (%): 230 [M+H]+ (100); ele-
mental analysis calcd (%) for C9H15N3O4·CF3CO2H (343.26): C 38.49; H
4.70; N 12.24; found: C 38.80; H 4.86; N 11.41.
5-(Diethoxy-phosphoryl)-4,5-dihydro-isoxazole-3-carboxylic acid ethyl
ester (4i): From diethyl vinyl phosphonate (2i; 69.6 mg, 0.424 mmol) and
ethyl nitroacetate (1; 85 mg, 0.636 mmol, 70 mL). After 15 h, the reaction
mixture was cooled and extracted with EtOAc (5ꢄ1.5 mL), the organic
phases were combined, dried over Na2SO4, filtered, and concentrated.
The residue was purified by chromatography on silica gel (Et2O; Rf =
0.27) to give 4i (73.7 mg, 62%) as a colorless oil. 1H NMR (400 MHz,
CDCl3): d=1.30–1.35 (m, 9H; 3ꢄCH2CH3), 3.42–3.52 (m, 2H; 4-H),
4.16–4.26 (m, 4H; 2ꢄPOCH2CH3), 4.32 (q, J=6.8 Hz, 2H; COCH2CH3),
4.86 ppm (t, J=10.8 Hz, 1H; 5-H); 13C NMR (100.58 MHz, CDCl3): d=
14.0 (q, COCH2CH3), 16.4 (q, POCH2CH3), 16.5 (q, POCH2CH3), 36.4 (t,
3-(Methylcarbamoyl)-4,5-dihydroisoxazole-5-carboxylic acid (13 f): From
acrylic acid (2 f; 30.5 mg, 0.424 mmol) and N-methyl nitroacetamide (10;
75.1 mg, 0.636 mmol). After 18 h, the reaction mixture was neutralized
with aqueous 4m NaOH, and washed with diethyl ether (4ꢄ1.5 mL). The
aqueous phase was acidified to pH 1 with aqueous 3m HCl, washed with
diethyl ether (4ꢄ1.5 mL), then extracted with ethyl acetate (5ꢄ1.5 mL).
The combined ethyl acetate extracts were dried (sodium sulfate), filtered,
and concentrated under reduced pressure to afford 13 f (55 mg, 76%) as
a clear oil that solidified on standing; m.p. 1578C (dec.); 1H NMR
(400 MHz, D2O): d=2.84 (s, 3H; CH3), 3.47 (unsymmetrical dd, J=6.8,
18.0 Hz, 1H; 4-H), 3.66 (unsymmetrical dd, J=12.3, 18.0 Hz, 1H; 4-H),
5.16 ppm (dd, J=6.8, 12.3 Hz, 1H; 5-H); 13C NMR (100.58 MHz, D2O):
d=26.4 (q, CH3), 38.4 (t, C-4), 79.8 (d, C-5), 154.8 (s, C-3), 161.8 (s,
CONH2), 174.6 ppm (s, CO2H); IR (KBr): n˜ =3700–2300 (br), 3345 (N-
H), 2622 (w), 1721 (s) (C=O), 1652 (s) (C=O), 1596 (w) (C=N), 1566 (w),
1421 (w), 1275 (w), 1248 (w), 1230 cmÀ1 (w); MS (EI): m/z (%): 142 (2),
127 (9) [MÀCO2H]+, 70 (8), 58 (100) [CONHMe]+; elemental analysis
calcd (%) for C6H8N2O4 (172.14): C 41.86, H 4.68, N 16.27; found: C
41.46, H 4.74, N 16.44.
N3-Methyl-4,5-dihydroisoxazole-3,5-dicarboxamide (13g): From acryla-
mide (2g; 30.1 mg, 0.424 mmol) and N-methyl nitroacetamide (10;
75.1 mg, 0.636 mmol). After 20 h, on cooling, the precipitated product
13g was collected, washed with cold H2O (1 mL), and oven-dried at
808C (1 h). The product (56 mg, 77%) was obtained as a white powder;
m.p. 192–1948C; 1H NMR (400 MHz, D2O): d=2.89 (s, 3H; NHCH3),
3.46 (unsymmetrical dd, J=6.8, 18.4 Hz, 1H; 4-H), 3.70 (unsymmetrical
dd, J=12.4, 18.4 Hz, 1H; 4-H), 5.32 ppm (dd, J=6.8, 12.4 Hz, 1H; 5-H);
13C NMR (100.59 MHz, D2O): d=26.5 (q, NHCH3), 38.8 (t, C-4), 80.4 (d,
C-5), 155.0 (s, C-3), 161.7 (s, CONHMe), 175.7 ppm (s, CONH2); IR
C-4), 62.3 (t, COCH2), 63.4 (t, J
ACHUTNGTRENN(GU C,P)=7.6 Hz, POCH2), 63.7 (t, JACTHUNGTRENNUNG
7.6 Hz, POCH2), 77.2 (d, J ACHTGNUTRENNUNG
T
6.9 Hz, C-3), 159.8 ppm (s, CO); 31P (80.96 MHz, CDCl3): d=17.4 ppm;
IR (CDCl3): n˜ =2984 (m), 2939 (w), 2909 (w), 1722 (s) (C=O), 1599 (w)
(C=N), 1253 cmÀ1 (s) (P=O); MS (ESI+): m/z (%): 302 [M+Na]+; ele-
mental analysis calcd (%) for C10H18NO6P (279.23): C 43.01, H 6.50, N
5.02; found: C 42.84, H 6.75, N 5.94.
N3,N5,N5-Trimethyl-4,5-dihydroisoxazole-3,5-dicarboxamide (13b): From
N,N-dimethylacrylamide (2b; 42 mg, 0.424 mmol) and N-methyl nitroace-
tamide (10; 75.1 mg, 0.636 mmol). After 20 h, the mixture was cooled
and treated with Ambersep 900 OH and concentrated under reduced
pressure to give 13b (67 mg, 79%) as
a
pale-yellow oil. 1H NMR
(400 MHz, CDCl3): d=2.85 (d, J=5.2 Hz, 3H; NHCH3), 2.94 (s, 3H;
NCH3), 3.10 (s, 3H; NCH3), 3.34 (dd, J=11.7, 17.9 Hz, 1H; 4-H), 3.85
(dd, J=7.8, 17.9 Hz, 1H; 4-H), 5.35 (dd, J=7.7, 11.7 Hz, 1H; 5-H),
6.66 ppm (br. s, 1H; NH); 13C NMR (100.58 MHz, CDCl3): d=26.0 (q,
NHCH3), 36.0 (t, C-4), 36.0 (q, NCH3), 37.1 (q, NCH3), 79.2 (d, C-5),
154.3 (s, C-3), 159.6 (s, CONHMe), 166.7 ppm (s, CONMe2); IR (CDCl3):
n˜ =3434 (m) (N-H), 2941 (w), 1662 (s) (C=O), 1602 (w) (C=N), 1543
(m), 1417 cmÀ1 (m); MS (EI): m/z (%)=199 (1) [M]+, 169 (4), 127 (37)
[MÀCONMe2]+, 72 (100) [CONMe2]+, 58 (97) [CONHMe]+; elemental
analysis calcd (%) for C8H13N3O3 (199.21): C 48.23, H 6.58, N 21.09;
found: C 46.34, H 6.71, N 21.09.
À
À
(KBr): n˜ =3402 (N H), 3328 (N H), 3206 (N-H), 2978, 1659 (C=O),
1597 (C=N), 1547, 1439 cmÀ1; MS (EI): m/z (%): 127 (14) [MÀCONH2]+
, 70 (10), 58 (100) [CONHMe]+, 44 (36) [CONH2]+; elemental analysis
calcd (%) for C6H9N3O3 (171.15): C 42.10, H 5.30, N 24.55; found: C
41.89, H 5.57, N 24.31.
5-Cyano-4,5-dihydro-N-methylisoxazole-3-carboxamide
(13c):
From
acrylonitrile (2c; 22.5 mg, 0.424 mmol) and N-methyl nitroacetamide (10;
125.1 mg, 1.06 mmol). After 24 h, aqueous 4.24m NaOH was added to
pH 8, and the mixture was washed with hexane (4ꢄ1.5 mL). The aqueous
phase was acidified to pH 1 with 3m HCl, washed with hexane (4ꢄ
1.5 mL) and then extracted with ethyl acetate (5ꢄ1.5 mL). The combined
extracts were dried (sodium sulfate), filtered, and concentrated under re-
duced pressure to give a yellow oil residue that was purified by chroma-
tography on silica gel (hexane/Et2O, 1:4 ; Rf =0.19) to yield 13c (50.6 mg,
0.330 mmol, 78%) as a colorless oil. 1H NMR (400 MHz, CDCl3): d=
2.92 (d, J=5.0 Hz, 3H; NHCH3), 3.62 (s, 1H; 4-H), 3.64 (d, J=2.7 Hz,
1H; 4-H), 5.33 (dd, J=5.6, 6.6 Hz, 1H; 5-H), 6.62 ppm (br. s, 1H; NH);
13C NMR (100.58 MHz, CDCl3): d=26.3 (q, NCH3), 40.0 (t, C-4), 67.8 (d,
C-5), 116.0 (s, CN), 153.4 (s, C-3), 158.2 ppm (s, CONHMe); MS (EI): m/
z (%): 153 (2) [M]+, 123 (8) [MÀNHMe]+, 98 (12), 70 (5), 58 (48)
[CONHCH3]+, 30 (100) [NHCH3]+; IR (CDCl3): n˜ =3434 (m) (N-H),
4,5-Dihydro-isoxazole-3,5-dicarboxylic acid 5-[(2-amino-ethyl)-amide] 3-
methylamide hydrochloride (13h·Cl): From 2-acryloylaminoethylammoni-
um 2h·Cl (63.8 mg, 0.424 mmol) and N-methyl nitroacetamide (10;
75.1 mg, 0.636 mmol). After 5 h, the mixture was filtered through a glass
Pasteur pipette filled with Ambersep 900 OHÀ resin (1 mL). The resin
was washed with H2O (3 mL) and the aqueous fractions were combined
and evaporated under reduced pressure. The residue was triturated with
Et2O, affording 4,5-dihydro-isoxazole-3,5-dicarboxylic acid 5-[(2-amino-
ethyl)-amide] 3-methylamide (88 mg, 99%) as a white powder. M.p. 140–
1
1448C (dec); H NMR (400 MHz, D2O): d=2.80–2.86 (m, 2H; CH2NH2),
2.88 (s, 3H; NHCH3), 3.30–3.49 (m, 3H; CH2NHCO and H-4), 5.32 ppm
Chem. Eur. J. 2013, 19, 665 – 677
ꢂ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
673

F. Machetti, F. De Sarlo et al.
(dd, J=7.2, 12.4 Hz, 1H; 5-H); 13C NMR (100.58 MHz, D2O): d=26.4 (q,
NCH3), 38.8 (t, C-4), 40.2 (t, CH2NH2), 41.5 (t, CH2NCO), 80.8 (d, C-5),
155.1 (s, C-3), 161.7 (s, CONHMe), 173.0 ppm (s, CONHCH2); IR (KBr):
n˜ =1667 (m), 1600 cmÀ1 (w); MS (ESI+): m/z (%): 215 [M+H]+ (100); el-
through a short pad of silica gel. On concentration, further 14g (19.1 mg)
was recovered as a white powder. Combined yield: 78%; m.p. 148–
1508C; 1H NMR (400 MHz, CDCl3): d=1.34 (t, J=7.2 Hz, 3H;
CH2CH3), 1.69 (s, 3H; CCH3), 3.10 and 3.65 (ABq, J=18.8 Hz, 2H; 4-
H), 4.34 (q, J=7.2 Hz, 2H; CH2CH3), 5.58 (br. s, 1H; NH2), 6.60 ppm
(br. s, 1H; NH2); 13C NMR (100.59 MHz, CDCl3): d=14.0 (q, CH2CH3),
23.8 (q, C-5CH3), 43.9 (t, C-4), 62.4 (t, CH2CH3), 89.7 (s, C-5), 152.5 (s,
C-3), 159.8 (s, CO2Et), 174.9 ppm (s, CONH2); IR (KBr): n˜ =3373 (s) (N-
H), 3178 (m) (N-H), 2996 (w), 2983 (w), 1726 (s) (C=O), 1693(s) (C=O),
1599 (m) (C=N), 1479 (w), 1411 (m), 1390 (m), 1271 cmÀ1 (s); MS (EI):
m/z (%): 200 (1) [M]+, 156 (13) [MÀCONH2]+, 155 (12) [MÀOEt]+, 84
(14), 73 (6) [CO2Et]+, 44 (42) [CONH2]+, 42 (100); elemental analysis
calcd (%) for C8H12N2O4 (200.19): C 48.00, H 6.04, N 13.99; found: C
47.83, H 5.91, N 13.85.
emental analysis calcd (%) for C8H14N4O3·CAHTUNGTRNE(NUNG 214.22): C 44.85, H 6.59, N
26.15; found: C 44.46, H 6.58, N 29.49.
The above amine (35 mg, 0.164 mmol) was dissolved in H2O (1 mL) and
3 N HCl (0.25 mL) was added. The mixture was evaporated and the resi-
due was triturated with Et2O, affording 13h·Cl (41 mg, 99%) as a white
powder. M.p. 170–1758C (dec); 1H NMR (400 MHz, D2O): d=2.88 (s,
3H; NHCH3), 3.48 (unsymmetrical dd, J=6.8, 18.4 Hz, 1H; 4-H), 3.22 (t,
J=5.6 Hz, 2H; CH2NH3+), 3.53–3.68 (m, 2H; CH2NHCO), 3.69 (unsym-
metrical dd, J=12.8, 18.4 Hz, 1H; 4-H), 5.36 ppm (dd, J=6.8, 12.4 Hz,
1H; 5-H); 13C NMR (100.58 MHz, D2O): d=26.5 (q, NCH3), 37.4 (t,
CH2NH3+), 38.7 (t, C-4), 39.6 (t, CH2NCO), 80.7 (d, C-5), 155.2 (s, C-3),
161.6 (s, CONHMe), 173.8 ppm (s, CONHCH2); IR (KBr): n˜ =3600–2660
Methyl 3-(methylcarbamoyl)-4,5-dihydro-5-methylisoxazole-5-carboxylate
(15a): From methyl methacrylate (2a; 42.4 mg, 0.424 mmol) and N-
methyl nitroacetamide (10; 75.1 mgmg, 0.636 mmol). After 16 h, the mix-
ture was extracted with EtOAc (4ꢄ1.5 mL), the combined extracts were
dried (sodium sulfate), filtered, and concentrated under reduced pres-
sure. The residue was dissolved in CH2Cl2 (2 mL) and washed with sat.
NaHCO3 (1ꢄ1.5 mL), dried over Na2SO4, filtered, and evaporated under
reduced pressure to afford 15a (66 mg, 77%) as a colorless oil. 1H NMR
(400 MHz, CDCl3): d=1.64 (s, 3H; C-5CH3), 2. 89 (d, J=4.8 Hz, 3H;
NHCH3), 3.12 and 3.69 (ABq, J=18.2 Hz, 2H; 4-H), 3.77 (s, 3H; OCH3),
6.66 ppm (br. s, 1H; NH); 13C NMR (100.56 Mz, CDCl3): d=23.3 (q, C-
5CH3), 26.0 (q, NCH3), 43.5 (t, C-4), 53.0 (s, OCH3), 88.0 (s, C-5), 153.4
(s, C-3), 159.7 (s, CONHMe), 171.4 ppm (s, CO2Me); MS (EI): m/z (%):
200 (<1) [M]+, 141 (6), 84 (15), 58 (100) [CONHCH3]+; IR: n˜ =3434
(m) (N-H), 2995 (w), 1742 (s) (C=O), 1671 (s) (C=O), 1600 (w) (C=N),
1542 (m), 1262 (m), 1202 cmÀ1 (m); elemental analysis calcd (%) for
C8H12N2O4 (200.19): C 48.00, H 6.04, N 13.99; found C 48.16, H 6.24, N
13.62.
(br), 1660 (s), 1596 (w), 1534 cmÀ1
.
Diethyl 3-(methylcarbamoyl)-4,5-dihydroisoxazol-5-ylphosphonate (13i):
From diethyl vinylphosphonate (2i; 69.6 mg, 0.424 mmol) and N-methyl
nitroacetamide (10; 75.1 mg, 0.636 mmol). After 15 h, the reaction mix-
ture was cooled, concentrated, and the residue was purified by chroma-
tography on silica gel (CHCl3/MeOH, 95:5; Rf =0.43) to give 13i
(106 mg, 94%) as a colorless oil. 1H NMR (400 MHz, D2O): d=1.39 (t,
1J
(m, 1H; 4-H), 3.66–3.78 (m, 1H; 4-H), 4.26–4.36 (m, 4H; 2ꢄ
POCH2CH3), 4.86 ppm (ddd, 2J(H,P)=12.4 Hz, 3J
(H,H)=9.2, 3.2 Hz,
1H; 5-H); 13C NMR (100.58 MHz, D2O): d=16.2 (q, POCH2CH3), 16.3
(q, POCH2CH3), 26.5 (q, CONHCH3), 36.4 (t, C-4), 65.7 (t, 2J
(C,P)=
4.6 Hz; POCH2), 65.8 (t, 2J
(C,P)=4.6 Hz; POCH2), 76.6 (d, J(C,P)=
168.6 Hz; C-5), 155.2 (s, 3J(C,P)=4.1 Hz; C-3), 161.4 ppm (s, CO); 31P
ACHTUNGTRENNUNG(H,H)=6.9 Hz, 6H; 2ꢄPOCH2CH3), 2.90 (s, 3H; NHCH3), 3.46–3.58
A
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
A
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
À
(80.95 MHz, D2O): d=19.3 ppm; IR (KBr): n˜ =3434 (m) (N H), 2984
(w), 2941 (w), 2910 (w), 1680 (s) (C=O), 1603 (w) (C=N), 1541 (m),
1251 cmÀ1 (s) (P=O); MS (ESI+): m/z (%): 287 [M+Na]+; elemental
analysis calcd (%) for C9H17N2O5P (264.22): C 40.91, H 6.49, N 10.60;
found: C 40.52, H 6.62, N 10.72.
3-(Methylcarbamoyl)-4,5-dihydro-5-methylisoxazole-5-carboxylic
acid
(15 f): From methacrylic acid (8 f; 36.5 mg, 0.424 mmol) and N-methyl ni-
troacetamide (10; 75.1 mg, 0.636 mmol). After 24 h, the reaction mixture
was made alkaline (pH 8) with 4.24m NaOH, and washed with Et2O (4ꢄ
1.5 mL); the aqueous phase was acidified to pH 1 with 3 N HCl and
washed with hexane (4ꢄ1.5 mL). The aqueous phase was evaporated to
dryness and purified by chromatography on silica gel (CHCl3/MeOH/
AcOH, 9:0.9:0.1; Rf =0.09) to give 15 f (69 mg, 88%) as a white powder;
m.p. 133–1358C. 1H NMR (300 MHz, D2O): d=1.61 (s, 3H; C-5CH3),
2.79 (s, 3H; CH3NH), 3.21 and 3.61 ppm (ABq, J=18.4 Hz, 2H; H-4);
13C NMR (50.29 MHz, D2O): d=23.3 (q, C-5CH3), 26.4 (q, NCH3), 43.7
(t, C-4), 89.1 (s, C-5), 154.9 (s, C-3), 161.9 (s, CONHMe), 176.4 ppm (s,
CO2H); IR (KBr): n˜ =3600–2300 (br), 2981 (m), 2943 (m), 1734 (m) (C=
O), 1670 (s) (C=O), 1597 (w) (C=N), 1558 (m), 1413 (w), 1272 cmÀ1; MS
(EI): m/z (%): 156 (2) [MÀNHMe]+, 141 (8) [MÀCO2H]+, 84 (15), 58
(100) [CONHMe]+, 45 (10) [CO2H]+, 43 (55); MS (ESIÀ): m/z (%): 185
(100) [MÀH]À; elemental analysis calcd (%) for C7H10N2O4 (186.17): C
45.16, H 5.41, N 15.05; found: C 45.40, H 5.12, N 15.24.
5-Methyl-4,5-dihydro-isoxazole-3,5-dicarboxylic acid 3-ethyl ester 5-methyl
ester (14a): From methyl methacrylate (8a; 42.5 mg, 0.424 mmol, 45 mL)
and ethyl nitroacetate (1; 85 mg, 0.636 mmol, 70 mL). After 20 h, the reac-
tion mixture was extracted with Et2O (4ꢄ1.5 mL). The combined organic
phases were dried over Na2SO4, filtered, and concentrated under reduced
pressure to give the product 14a (67 mg, 73%) as a yellow oil. Elemental
analysis calcd (%) for C9H13NO5 (215.20): C 50.23, H 6.09, N 6.51; found:
C 49.85, H 5.92, N 6.95. The spectral data are identical to those previous-
ly reported.[7]
3-(Ethoxycarbonyl)-5-methyl-4,5-dihydroisoxazole-5-carboxylic
acid
(14 f): From methacrylic acid (8 f; 36.5 mg, 0.424 mmol, 36 mL) and ethyl
nitroacetate (1; 85 mg, 0.636 mmol, 70 mL). After 72 h, the reaction mix-
ture was concentrated under reduced pressure and the residue was mixed
with EtOAc (6 mL). The obtained suspension was stirred for a few mi-
nutes at RT. After filtration, the organic phase was concentrated under
reduced pressure to give 14 f (55 mg, 65%) as a yellowish oil. 1H NMR
(400 MHz, CDCl3): d=1.33 (t, J=6.9 Hz, 3H; CH2CH3), 1.69 (s, 3H;
CCH3), 3.10 and 3.69 (ABq, J=18.0 Hz, 2H; 4-H), 4.35 ppm (q, J=
6.9 Hz, 2H; CH2CH3); 13C NMR (100.58 MHz, CDCl3): d=14.0 (q,
CH2CH3), 23.2 (q, C-5CH3), 43.4 (t, C-4), 62.4 (t, CH2CH3), 88.1 (s, C-5),
151.2 (s, C-3), 159.9 (s, CO2Et), 174.8 ppm (s, CO2H); MS (EI): m/z (%):
156 (54) [MÀCO2H]+, 84 (39), 69 (28), 45 (49), 42 (100); IR (neat): n˜ =
3600–2400 (broad signal), 2985 (w), 2939 (w), 1728 (s) (C=O), 1597 (w)
(C=N), 1380 (w), 1269 cmÀ1 (m); elemental analysis calcd (%) for
C8H11NO5 (201.18): C 47.76; H 5.51, N 6.96; found: C 48.03, H 5.94, N
7.16.
N3,5-Dimethyl-4,5-dihydroisoxazole-3,5-dicarboxamide
(15g):
From
methacrylamide (8g; 36.1 mg, 0.424 mmol) and N-methyl nitroacetamide
(10; 75.1 mg, 0.636 mmol). After 20 h, the reaction mixture was cooled
and kept at 48C overnight. The precipitate was collected and washed
with cold H2O (1 mL) then oven-dried at 508C to afford the product 15g
(44.7 mg). The aqueous fractions were combined and evaporated to dry-
ness. The residue was dissolved in CHCl3 and filtered through a short
pad of silica gel. The solvent was evaporated under reduced pressure to
give further 15g (31.6 mg) as a white solid. Combined yield: 98%; m.p.
209–2128C. 1H NMR (400 MHz, D2O): d=1.70 (s, 3H; C-5CH3), 2.88 (s,
3H; CH3NH), 3.32 and 3.62 ppm (ABq, J=18.2 Hz, 2H; 4-H); 13C NMR
(D2O): d=23.6 (C-5CH3), 26.5 (NHCH3), 44.1 (t, C-4), 89.6 (s, C-5),
Ethyl 5-carbamoyl-5-methyl-4,5-dihydroisoxazole-3-carboxylate (14g):
From methacrylamide (8g; 36.1 mg, 0.424 mmol) and ethyl nitroacetate
(1; 85 mg, 0.636 mmol, 70 mL). After 6 h, the reaction mixture was cooled
and kept at 48C overnight. The precipitate was collected, washed with
cold H2O (1 mL), and then oven dried at 808C (3 h) to give 14g
(47.4 mg) as a white powder. The aqueous fractions were combined and
evaporated to dryness. The residue was dissolved in CHCl3 and filtered
155.5 (s, C-3), 162.0 (s, CONHMe), 178.5 ppm (s, CONH2); IR: n˜ =3404
À1
À
(N-H), 3369 (N H), 2984, 1658 and 1636 (C=O), 1608 cm (C=N); MS
(EI): m/z (%): 141 (8) [MÀCONH2]+, 84 (15), 58 (100) [CONHMe]+, 44
(36) [CONH2]+; elemental analysis calcd (%) for C7H11N3O3 (185.18): C
45.40, H 5.99, N 22.69; found: C 45.05, H 6.22, N 22.93.
674
www.chemeurj.org
ꢂ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2013, 19, 665 – 677

Aqueous Reactions of Nitro Compounds
FULL PAPER
3-Butylcarbamoyl-5-methyl-4,5-dihydro-isoxazole-5-carboxylic
acid
Compound 20a: 1H NMR (400 MHz, CDCl3): d (selected signals from
the mixture)=3.02 (d, J=5.2 Hz, 3H; NCH3), 3.91 (s, 3H; OCH3),
9.00 ppm (s, 1H; 5-H).
methyl ester (16a): From methyl methacrylate (8a; 42.5 mg, 0.424 mmol,
44 mL) and N-butylnitroacetamide (11; 101.8 mg, 0.636 mmol, 70 mL).
After 24 h, the reaction mixture was cooled and extracted with EtOAc
(4ꢄ10 mL). The combined organic phases were dried over Na2SO4, fil-
tered, and concentrated under reduced pressure. The residue was dis-
solved in CH2Cl2 (2 mL) and washed with sat. NaHCO3 (1ꢄ1.5 mL),
dried over Na2SO4, filtered, and evaporated under reduced pressure to
3-Methylcarbamoyl-isoxazole-5-carboxylic acid (19 f) and 3-methylcarba-
moyl-isoxazole-4-carboxylic acid (20 f): From propiolic acid (18 f;
29.7 mg, 0.424 mmol) and N-methyl nitroacetamide (10; 75.1 mg,
0.636 mmol). After 168 h, the reaction mixture was cooled and concen-
trated under reduced pressure and the residue was purified by chroma-
tography on silica gel (CHCl3/MeOH/AcOH, 8:1.8:0.2) to give a first
fraction (12 mg; Rf =0.2) containing traces of isoxazole 20 f, and a second
fraction containing pure isoxazole 19 f (54 mg, 75%; Rf =0.08).
Compound 19 f: White powder; m.p. 1858C (dec.). 1H NMR (400 MHz,
D2O): d=2.97 (s, 3H; NHCH3), 7.10 ppm (s, 1H; 4-H); 13C NMR
(100.58 MHz, D2O): d=26.6 (q, NCH3), 105.9 (s, C-4), 159.4 (s), 161.9
(s), 163.0 (s), 168.0 ppm (s, CO2H); IR (KBr): n˜ =3600–2600 (br), 1678,
1622 cmÀ1; MS (ESIÀ): m/z (%): 169 (100) [MÀH]À; elemental analysis
calcd (%) for C6H6N2O4 (170.12): C 42.36, H 3.55, N 16.47; found: C
42.68, H 3.55, N 16.33.
afford 16a (66 mg, 65%) as
a
pale-yellow oil. 1H NMR (400 MHz,
CDCl3): d=0.90 (t, J=7.4 Hz, 3H; CH2CH3), 1.28–1.38 (m, 2H;
CH2CH3), 1.46–1.55 (m, 2H; NHCH2CH2), 1.63 (s, 3H; C-5CH3), 3.12
and 3.71 (ABq, J=18.3 Hz, 2H; H-4), 3.30 (q, J=5.8 Hz, 1H;
CONHCH2), 3.76 (s, 3H; OCH3), 6.59 ppm (br. s, 1H; NH); 13C NMR
(100.6 MHz, CDCl3): d=13.6 (q, CH3), 19.9 (t, CH3CH2), 23.4 (q, C-
5CH3), 31.4 (t, NHCH2CH2), 39.2 (t, CONHCH2), 43.6 (t, C-4), 53.0 (q,
OCH3), 88.0 (s, C-5), 153.6 (s, C-3), 159.0 (s, CONHBu), 171.4 ppm (s,
À
CO2Me); IR (CDCl3): n˜ =3421 (m) (N H), 2958 (m), 2934 (m), 1742 (s)
(OC=O), 1676 (s) (NC=O), 1599 (w) (C=N), 1202 cmÀ1 (w); MS (EI): m/
z (%): 242 (<1) [M]+, 199, (2) [MÀPr]+, 183 (4) [MÀCO2Me]+, 170 (6),
84 (8), 100 (22) [CONHBu]+, 57 (100); elemental analysis calcd (%) for
C11H18N2O4 (242.27): C 54.53, H 7.49, N 11.56; found: C 54.21, H 7.76, N
11.99.
Compound 20 f: 1H NMR (200 MHz, D2O): d (selected signals from the
mixture)=2.95 (s, 3H; NHCH3), 9.05 ppm (s, 1H; 5-H).
Scale up for the reactions between methacrylamide (8g) and ethyl nitroa-
cetate (1) or N-methyl nitroacetamide (10):
5-Methyl-4,5-dihydro-isoxazole-3,5-dicarboxylic acid 5-amide 3-[(2-ami-
noethyl)amide] hydrochloride (17g·Cl): From methacrylamide (8g;
36.1 mg, 0.424 mmol) and N-aminoethyl nitroacetamide hydrochloride
(12·Cl; 116.4 mg, 0.636 mmol). After 24 h, the reaction mixture was
cooled, washed with diethyl ether (4ꢄ1.5 mL), and the aqueous phase
was concentrated. The residue was dissolved in MeOH (12 mL) and
treated with ambersep 900. After evaporation of the methanolic solution,
5-methyl-4,5-dihydro-isoxazole-3,5-dicarboxylic acid 5-amide 3-[(2-ami-
noethyl)amide] (83 mg, 92%) was obtained as a colorless oil. 1H NMR
(200 MHz, D2O): d=1.69 (s, 3H; CH3), 2.85 (t, J=6.2 Hz, 2H;
NH2CH2), 3.42 (t, J=6.2 Hz, 2H; CONHCH2), 3.29 and 3.62 ppm (ABq,
J=18.4 Hz, 2H, 4-H); 13C NMR (100.58 MHz, D2O): d=23.4 (q, CH3),
39.4 (t, CONHCH2), 39.8 (t, NH2CH2), 43.9 (t, C-4), 89.7 (s, C-5), 155.3
(s, C-3), 162.1 (s, CONH), 178.3 ppm (s, CONH2); MS (ESI+): m/z (%):
237 (100) [M+Na]+, 215 (74) [M+H]+; elemental analysis calcd (%) for
C8H14N4O3 (214.22): C 44.85, H 6.59, N 26.15; found: C 45.13, H 6.34, N
25.94.
Ethyl 5-carbamoyl-4,5-dihydro-5-methylisoxazole-3-carboxylate (14g):
Methacrylamide (8g; 361 mg, 4.24 mmol) was added to a mixture of
aqueous 4.24m NaOH (0.10 mL, 0.424 mmol), ethyl nitroacetate (1;
678 mg, 5.09 mmol) and water (13.9 mL), and the reaction mixture was
vigorously stirred in a sealed tube at 608C. After 22 h, the reaction mix-
ture was cooled and kept in the refrigerator (48C) overnight. The precipi-
tate was collected, washed with H2O (3ꢄ5 mL) and oven-dried at 808C,
affording 14g (549 mg) as white powder. The mother solution combined
with washings was extracted with CHCl3 (3ꢄ10 mL). The combined or-
ganic fractions were dried over Na2SO4, filtered, and evaporated to dry-
ness. The residue was washed with Et2O (5 mL), giving further 14g
(101 mg) as a white powder. Overall yield 77%. Elemental analysis calcd
(%) for C8H12N2O4 (200.19): C 48.00, H 6.04, N 13.99; found: C 47.83, H
5.91, N 13.85. The spectral data are identical to those reported above.
4,5-Dihydro-N3,5-dimethylisoxazole-3,5-dicarboxamide (15g): The same
procedure applied to N-methyl nitroacetamide (10; 600 mg, 5.09 mmol)
afforded 15g (531 mg) as a white powder. The mother solution combined
with washings was evaporated to dryness. The residue was washed with
EtOAc (5 mL) and CHCl3 (5 mL) to give further 15g (109 mg). Overall
yield 82%. Elemental analysis calcd (%) for C7H11N3O3 (185.18): C
45.40, H 5.99, N 22.69; found: C 45.05, H 6.22, N 22.93. The spectral data
are identical to those reported above.
The above amine (78 mg) was treated with 3 N HCl to give 17g Cl in
1
quantitative yield; m.p. 2058C (dec.). H NMR (400 MHz, D2O): d=1.70
(s, 3H; CH3), 3.25 (t, J=6.2 Hz, 2H; NH2CH2), 3.67 (t, J=6.2 Hz, 2H;
CONHCH2), 3.32 and 3.63 ppm (ABq, J=17.2 Hz, 2H; 4-H); 13C NMR
(100.58 MHz, D2O): d=23.5 (q, CH3), 40.2 (t,CONHCH2), 41.8 (t,
NH2CH2), 43.9 (t, C-4), 89.5 (s, C-5), 155.2 (s, C-3), 161.5 (s, CONH),
178.0 ppm (s, CONH2); IR (KBr): n˜ =3500–2500 (br), 1668 cmÀ1 (C=O)
(s); elemental analysis calcd (%) for C8H14N4O3·HCl (250.68): C 38.33, H
6.03, N 22.35; found: C 38.46, H 5.99, N 22.59.
Condensation of Fumaric acid (21) with N-methyl nitroacetamide (10):
trans-3-Methylcarbamoyl-4,5-dihydroisoxazole-4,5-dicarboxylic acid (22),
cis-3-methylcarbamoyl-4,5-dihydroisoxazole-4,5-dicarboxylic acid (23),
and 3-methylcarbamoyl-4,5-dihydroisoxazole-5-carboxylic acid (13 f):
From fumaric acid (21; 49.2 mg, 0.424 mmol) and N-methyl nitroaceta-
mide (10; 125.1 mg, 1.06 mmol) and NaOH 4.24m (10 mL, 0.0424 mmol).
After 7 days, the reaction mixture was cooled and concentrated under re-
duced pressure and the residue was purified by chromatography on silica
gel (CHCl3/iPrOH 95:5 to CHCl3/iPrOH/AcOH 48:48:2). The main trans
isomer 22, collected at about Rf =0.19, contained in the head fractions
(23 mg, ca. 25%) the decarboxylated isoxazoline 13f (detected by
1H NMR spectroscopic analysis, less than 4%) and in the tail fractions
3-Methylcarbamoyl-isoxazole-5-carboxylic acid methyl ester (19a) and 3-
methylcarbamoyl-isoxazole-4-carboxylic acid methyl ester (20a): From
methyl propiolate (18a; 35.6 mg, 0.424 mmol) and N-methyl nitroaceta-
mide (10; 75.1 mg, 0.636 mmol). After 22 h, the reaction mixture was
cooled to 48C for 4 h. The precipitate was separated by centrifugation
and oven-dried at 808C to afford 19a (31 mg, 0.168 mmol, 39%) as a
white powder. The water supernatant was extracted with CHCl3 (5ꢄ
1.5 mL) and the combined organic phases were dried over Na2SO4, fil-
tered, and evaporated to yield the two regioisomers (19a/20a, 3:7; 25 mg,
0.136 mmol, 32%). Overall yield 71%.
Compound 19a: White powder; m.p. 158–1608C; 1H NMR (400 MHz,
CDCl3): d=3.00 (d, J=5.2 Hz, 3H; NCH3), 3.97 (s, 3H; OCH3), 6.84
(br. s, 1H; NH), 7.32 ppm (s, 1H, 4-H); 13C NMR (100.58 MHz, CDCl3):
d=26.2 (q, NCH3), 53.1 (q, OCH3), 108.9 (s, C-4), 156.6 (s, CO2CH3),
158.3. (s, CONHCH3), 159.0 (s, C-3 or C-5), 161.4 ppm (s, C-3 or C-5);
IR (KBr): n˜ =3271 (br), 3114 (m), 2960 (m), 1731 (OC=O) (s), 1650
(NC=O) (s), 1605 (C=N) (w), 1573 (m), 1289 cmÀ1 (br, s); MS (EI): m/z
(%): 154 (2) [MÀNHMe]+, 125 (13) [MÀCO2Me]+, 68 (19), 58 (100)
[CONHMe]+; elemental analysis calcd (%) for C7H8N2O4 (184.15): C
45.66, H 4.38, N 15.21; found: C 45.44, H 4.29, N 15.23.
1
(36 mg, 40%) the cis isomer 23 (detected by H NMR spectroscopic anal-
ysis, less than 10%).
Compound 22: Sticky oil; 1H NMR (400 MHz, D2O): d=2.90 (s, 3H;
NHCH3), 4.30 (d, J=5.6 Hz, 1H; 4-H), 5.21 ppm (d, J=5.6 Hz, 1H; 5-H);
13C NMR (50 MHz, D2O): d=26.4 (q, NCH3), 60.1 (d, C-4), 86.5 (d, C-5),
153.9 (s, C-3), 161.7 (s, CONH), 175.0 (s, C-5CO2H), 176.6 ppm (s, C-
4CO2H); IR (KBr): n˜ =3600–2800 (br), 1730 (s), 1660 cmÀ1 (s); MS
(ESIÀ): m/z (%): 215 [MÀH]À; elemental analysis (with 23) calcd (%) for
C7H8N2O6 (216.15): C 38.90, H 3.73, N 12.96; found: C 38.64, H 3.93, N
12.74.
Chem. Eur. J. 2013, 19, 665 – 677
ꢂ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
675

F. Machetti, F. De Sarlo et al.
Compound 23: Identified signals. 1H NMR (400 MHz, D2O): d=2.89 (s,
3H; NHCH3), 4.46 (d, J=12.0 Hz, 1H; 4-H), 5.30 ppm (d, J=12.0 Hz,
1H; 5-H).
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Acknowledgements
The authors thank the Ministero dell’Istruzione, Universitꢁ e Ricerca
(MIUR, Italy project COFIN 2008-prot. 200859234J) for financial sup-
port and a fellowship to L.G. B. Innocenti and M. Passaponti (Universitꢁ
di Firenze) are acknowledged for their technical support. Financial sup-
port by the Ente Cassa di Risparmio di Firenze for the purchase of the
Karl Fisher coulometer is gratefully acknowledged. We also thank Giaco-
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1
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[56] Previously described as an oil in ref. [22].
Received: July 27, 2012
Revised: August 29, 2012
Published online: November 14, 2012
Chem. Eur. J. 2013, 19, 665 – 677
ꢂ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
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