Synthesis of 4,5-dihydroisoxazoles by condensation of primary nitro compounds with alkenes by using a copper/base catalytic system

Article abstract of DOI:10.1002/chem.200800554

A new procedure for the synthesis of 4.5-dihydroisoxazoles by condensation of primary nitro compounds with olefins by using a copper/base catalytic system is described. The catalytic effect of copper(II) salts is evidenced by comparison of the reaction ra

Full text of DOI:10.1002/chem.200800554

FULL PAPER
DOI: 10.1002/chem.200800554
Synthesis of 4,5-Dihydroisoxazoles by Condensation of Primary Nitro
Compounds with Alkenes by Using a Copper/Base Catalytic System
Luca Cecchi,[a] Francesco De Sarlo,*[a] and Fabrizio Machetti*[b]
Abstract: A new procedure for the syn-
thesis of 4.5-dihydroisoxazoles by con-
densation of primary nitro compounds
with olefins by using a copper/base cat-
alytic system is described. The catalytic
effect of copper(II) salts is evidenced
by comparison of the reaction rates.
Thus, activated nitro compounds react
faster than with organic catalysis by
tertiary amines, whereas nitroalkanes,
unable to condense with dipolarophiles
in the presence of the base alone, un-
dergo the reaction on addition of a
copper(II) catalyst. The observed oc-
currence of induction periods in most
reactions is ascribed to an equilibrium
preceding the rate-determining step,
and gives a hint as to the proposed re-
action mechanism. The results indicate
that this method might be of practical
and general utility for synthetic prac-
tice.
Keywords: catalysis
· copper ·
cycloaddition · dihydroisoxazoles ·
nitro compounds
Introduction
On the other hand, dehydration of primary nitro com-
pounds with the production of isoxazole derivatives has also
been observed as a side process during the radical addition
of nitro compounds to alkenes caused by MnIII salts. “Acti-
vated” nitro compounds (a-nitroketones, nitroacetamides[23]
or nitroacetates),[24,25] on treatment with an alkene and
MnIII, according to the reported rationalisation, follow two
parallel reaction paths: the intermediate MnIII nitronate
reacts with the alkene to give either the expected radical ad-
dition or the dehydrated cycloadduct. In the first reaction,
MnIII behaves as a monoelectronic oxidant, in the other, as a
dehydrating agent.[25]
1,3-Dipolar cycloadditions are a powerful method for assem-
bling heterocyclic rings with high regio- and stereocontrol.[1]
Primary nitro compounds are extensively used as starting
materials for the synthesis of 4,5-dihydroisoxazoles via inter-
mediate nitrile oxides;[2] on treatment with various reagents,
such as aryl isocyanates,[3–9] inorganic[10,11] and organic[12–15]
chlorides or organic anhydrides,[16,17] in the presence of a di-
polarophile and often a base, the isoxazole derivatives are
produced besides the discarded material derived from the
reagent employed [Eq. (1)].[18] From the same nitro com-
pounds, 4,5-dihydroisoxazoles can also be prepared via
alkyl[19,20] or silyl[21,22] nitronates by cycloaddition and subse-
quent elimination of alcohol or silanol, respectively.
We have recently reported a convenient procedure for the
condensation of primary nitro compounds with alkynes (to
isoxazoles) or alkenes (to isoxazolines) under base cataly-
sis.[26–29] This method avoids the use of a dehydrating agent,
but requires a catalytic amount of a suitable organic base in-
[a] Dr. L. Cecchi, Prof. F. De Sarlo
Dipartimento di Chimica Organica “U. Schiff”
Università di Firenze, Via della Lastruccia 13
50019 Sesto Fiorentino, Firenze, (Italy)
Fax : (+39)055-457-3531
E-mail: fdesarlo@unifi.it
stead, such as 1,4-diazabicycloACTHRE[UNG 2.2.2]octane (DABCO) or 1-
[b] Prof. Dr. F. Machetti
methylimidazole. This process appears to occur without the
formation of intermediate nitrile oxides and it can be re-
garded as a condensation process [Eq. (2), EWG=electron-
withdrawing group], in which cycloaddition of the inter-
mediate dipole (nitronate) precedes water release. The use
of a catalytic organic base instead of stoichiometric polluting
Istituto di Chimica dei Composti Organometallici del Consiglio
Nazionale delle Ricerche c/o Dipartimento di Chimica Organica “U.
Schiff”
Università di Firenze, Via della Lastruccia 13
50019 Sesto Fiorentino, Firenze, (Italy)
Fax : (+39)055-457-3531
E-mail: fabrizio.machetti@unifi.it
Chem. Eur. J. 2008, 14, 7903 – 7912
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
7903

reagents makes this procedure more benign towards the en-
vironment and represents another step forward towards
atom economy.[30]
able to catalyse the condensation of a broad range of nitro-
alkanes with different functionalised dipolarophiles.
Results and Discussion
The mentioned reaction between norbornene and nitro-
ethane was assumed as a model: in view the above previous
results, various metal salts or complexes were added to this
mixture (0.05 molar ratio with respect to the dipolarophile)
and the eventual conversion into the condensation product
verified after 20 h. No conversion was observed upon addi-
tion of the following salts or complexes: AgOAc, AgOTf,
However, the reaction is applicable to “activated” nitro
compounds (nitroacetate derivatives, a-nitroketones or phe-
nylnitromethane) but fails with nitroalkanes.[26–29] Thus, on
treatment of norbornene (0.3m in CHCl3) with nitroethane
and DABCO (molar ratio 1:2.5:0.5) at 608C for 72 h, no
Co
Ni(OAc)2, [Pt
hexylphosphine)benzylidine ruthenium(IV) chloride, Sc-
(OTf)3 and Yb(OTf)3. Yet encouragingly, results were ob-
A
(OAc)3, Fe
G
ACHTRE(UNG OTf)3, MgBr2,
1
condensation was observed by H NMR spectroscopic analy-
A
N
ACHTREUNG
sis (Table 1, entry 1). In this paper, we describe a new
method leading to substituted 4,5-dihydroisoxazoles based
on a copper/base catalytic system. This catalytic system is
A
ACHTREUNG
tained by addition of a nickel complex or salts of copper
and palladium (Table 1). Among them, it was found that
only copper salts gave significant conversions without coun-
ter-anion effects (Table 1, entries 4–6).
Table 1. Catalytic activities of selected metal salts or complexes in the re-
action of norbornene with nitroethane.[a]
The reaction conducted with copper(II) acetate in the ab-
sence of base showed no conversion (Table 1, entry 2). A
trace of product was observed with the [NiCAHTRE(UGN PPh3)4] complex,
after 72 h, along with traces of other unidentified com-
pounds (Table 1, entry 3).
Entry[a]
Metal
none
t [h]
Conv. [%][b]
1
72
72
72
20 (40)
20
0
0
2[c]
3
Cu
[Ni
(OAc)2
Cu(OTf)2
Cu(CF3CO2)2
Pd(OAc)2
A
As concerns the use of palladium complex, a further ex-
periment was needed to possibly identify other products. In
fact Trost et al. reported a Pd0-catalysed cycloalkylation of
nitro compounds to isoxazoline-2-oxide.[31] The reaction with
palladium(II) acetate (Table 1, entry 7) was then repeated
on a larger scale and deeply examined, but only the 4,5-di-
hydroisoxazole cycloadduct was found.[32] It turned out that
copper(II) salts are excellent catalysts for these reactions.
Thus, the sluggish reaction between ethyl nitroacetate and
styrene with DABCO under the reported conditions gave a
50% conversion of dipolarophile into the corresponding cy-
cloadduct after 40 h, with an induction period of 16–18 h.
However, on addition of 5% copper(II) acetate, the conver-
sion reaches 60% after 8 h (see further discussions).
The effect is even more dramatic in the reaction of nitro-
pentane with methyl acrylate, which gives no cycloadduct
after 40 h in the presence of N-methylpiperidine (NMP), but
affords 100% cycloadduct after the same period if 5% of
copper(II) acetate is added to the mixture. Preliminary re-
sults have been published before the present work was com-
plete.[33]
Assuming as a model the reaction of norbornene and ni-
troethane mentioned above, a screening of bases was carried
out, in which DABCO was replaced by various bases, in the
presence of 0.05 equivalents of copper(II) acetate: the con-
version of dipolarophile into product after 40 h is reported
in Table 2.
The reaction in general fails with heteroaromatic bases
(Table 2, entries 1–3 and 5) with the sole exception of 1-
methylimidazole (entry 4). Low conversions are observed
with secondary amines, such as diethylamine and piperidine
C
trace
45 (55)
52
47 (56)
10
4Cu
5
6
N
ACHTREUNG
U
20 (40)
20
7
ACHTREUNG
[a] Reactions were carried out by using nitroethane/norbornene/DAB-
CO/ACHTREUNG[metal] in a 2.5:1:0.5:0.05 molar ratio. See the Experimental Section
for details. [b] Conversions are based on 1H NMR spectroscopic analysis.
[c] No base was used.
Abstract in Italian: E’ descritta una nuova procedura sinteti-
ca per la preparazione di 4,5-diidroisossazoli attraverso la
condensazione di nitrocomposti primari con olefine. Il
metodo si basa sull’utilizzo di un sistema catalitico costituito
da rame(II)accompagnato da una base organica. L ’effetto
catalitico dei sali di rame(II)› stato evidenziato confrontan-
do le velocità di conversione per alcune reazioni modello. In-
fatti, i nitrocomposti attivati reagiscono piœ velocemente che
non in sola presenza di ammine terziarie mentre i nitroalcani,
i quali non condensano con i dipolarofili in presenza della
sola base, reagiscono per aggiunta di rame(II). Queste reazio-
ni di condensazione hanno mostrato la presenza di tempi
d’induzione variabili in funzione dei substrati e della tipolo-
gia di rame utilizzata. Il tempo d’induzione › imputabile a
pre-equilibri che precedono lo stadio lento della reazione e
sono in accordo con il meccanismo di reazione proposto. I ri-
sultati ottenuti mostrano che questo metodo › pratico e di uti-
lità generale per la sintesi organica.
7904
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Chem. Eur. J. 2008, 14, 7903 – 7912

Synthesis of 4,5-Dihydroisoxazoles
FULL PAPER
Table 2. Catalytic activities of various bases in the reaction of norbor-
nene with nitroethane promoted by copper(II) acetate.
Table 3. Optimisation of reaction conditions: base/metal molar ratio and
concentration of dipolarophile.[a]
[b]
Entry[a]
Base
pKBH+
Conv. [%][c]
Entry
Base
Base/Cu
(OAc)2
Norbornene [mm]
Conv. [%][b]
1
2
3
2,2’-bipyridine
pyridine
4.40
5.23
7.00
4
7.18
7.41
7.67
7.97
8.61
8.86
8.86
9.52
9.58
9.83
9.88
9.91
0
0
0
1
2
3
NMP
NMP
NMP
0.1:0.05
NMP
NMP
NMP
NMP
NMP
NMP
DBU
DBU
DBU
0.1:0.05
DBU
1:0.05
0.5:0.05
0.2:0.05
304100
(92) 30494
30465
2-DMAP[d]
41-methylimidazole
5
6
7
8
9
(33)
7.014
4NMP
5
6
7
8
9
10
11
12
13
14DBU
15
304 56
imidazole
4-methylmorpholine
Me2NCH2NMe2
4-(1-pyridinyl)morpholine
1,4-dimethylpiperazine
1,2-dimethylimidazole
Me2NCH2CH2NMe2
4-DMAP[e]
0
0.05:0.05
1:0.05
4
3044
608
608
608
608
27 (19)
37 (19)
46 (43)
82 (68)
59 (49)
26 (22)
54(48)
58 (52)
87 (64)
92 (60)
74(64)
95 (94)
100 (84)
78 (62)
85 (82)
71 (53)
32 (30)
76 (66)
46 (33)
100 (100)
98 (92)
72 (68)
59 (56)
41 (30)
0.5:0.05
0.2:0.05
0.1:0.05
0.05:0.05
1:0.05
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
608
30482 (78)
) 30483 (84
30476 (70)
66 (58)
2) 30451 (4
0.5:0.05
0.2:0.05
4-(1-pyrrolidinyl)pyridine
nBuMe2N
304
Me2N
A
0.05 0.05
iPrMe2N
NMP
[a] Reactions were carried out by using nitroethane/norbornene in a
2.5:1.0 molar ratio. See the Experimental Section for more details.
[b] The reported conversions are based on 1H NMR spectroscopic analy-
sis.
9.91
9.99
1-ethylpiperidine
Et3N
1-methylpyrrolidine
cyclohexyldimethylamine
Et2NH
quinuclidine
iPr2EtN
piperidine
tropane
10.62
10.62
10.72
10.76
10.87
10.98
11.2431 (31)
11.56
12.40
13.27
14.37
14.47
44%), without significant change when the solution is more
concentrated (entries 6–10, 0.6m). A similar trend is ob-
served with a stronger base, such as DBU (entries 11–15).
However, at low base concentrations, decomposition of ni-
troethane was not severe; therefore, prolonged reaction
times ensure complete conversion. These results indicate
that the best molar ratio is in the range of 0.5–0.2 base/0.05
copper.
– (90)[f]
70 (52)
– (84)[f]
– (83)[f]
74 (71)
proton sponge
DBU[g]
MTBD[h]
TBD[i]
[a] Reactions were carried out by using nitroethane/norbornene/base/Cu-
ACHTREUNG(OAc)2 in a 2.5:1.0:0.5:0.05 molar ratio. See the Experimental Section for
To establish the influence of the copper source on the
process, a different dipolarophile/dipole pair was chosen. A
less-reactive dipolarophile, such as ethyl vinyl ether, and a
more-stable nitroalkane, such as nitropentane (see later),
was utilised to fine-tune the reaction conditions. The per-
centage conversion of dipolarophile after established inter-
vals was evaluated in the presence of different copper sour-
ces (Table 4).
more details. [b] Calculated by using Advanced Chemistry Development
(ACD/Labs) Software V8.14for Solaris (1994–2007 ACD/Labs). [c] The
reported conversions are based on 1H NMR spectroscopic analysis. In
brackets the conversion observed after 20 h. [d] 2-Dimethylaminopyri-
dine. [e] 4-Dimethylaminopyridine. [f] Excess nitroethane was completely
deomposed after 20 h, therefore the conversion could no longer increase.
[g] 1,8-Diazabicyclo
ACHTREUNG
A
(entries 22 and 25). No definite trend is apparent with other
bases, as the results are not related to their strength, to H-
bonding ability or to the presence of more than one basic
centre.[28] Since very strong bases cause faster decomposition
of nitroethane, NMP (entry 17) has been chosen for further
experiments. This base, tetramethylpropanediamine and 1-
ethylpiperidine (entries 15 and 18, respectively) represent
the right balance in terms of high conversion and low de-
composition of nitroethane.
Table 4. Influence of the copper source on the condensation of nitropen-
tane with ethyl vinyl ether. Conversion into product by using an excess of
nitropentane.[a]
Entry [Cu]
Conv. [%][b] Entry [Cu]
Conv. [%][b]
53 (48)
1
Cu
A
6
CuACHTER(UNG OTf)2
2
3
4Cu
5
CuOAc
71 (51)
75 (55)
63 (62)
48 (45)
The effect of the base/copper ratio and of reagent concen-
trations on the above model reaction was investigated next
(Table 3). The conversion observed after 40 h (0.3m norbor-
nene (1 equiv) in CHCl3; + nitroethane, 2.5 equiv + cop-
per(II) acetate, 0.05 equiv) decreases as the equivalents of
NMP are reduced from one equivalent (entry 1, 100%) to
0.5 (entry 2, 94%) and then to 0.05 equivalents (entry 5,
Cu0[c]
7
8
9
CuO
CuCl2
CuACHTRE(NUG CF3CO)2 56 (50)
0
0[d]
58 (55)
CuI
[a] Reactions were carried out by using nitropentane/ethyl vinyl ether/
NMP/[Cu] in a 2.5:1.0:0.5:0.05 molar ratio. See the Experimental Section
for more details. [b] Conversions are based on 1H NMR spectroscopic
analysis. In brackets: conversion after 20 h. [c] Powder. [d] Wire.
Chem. Eur. J. 2008, 14, 7903 – 7912
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7905

F. Machetti, F. De Sarlo, and L. Cecchi
The oxidation state has apparently no influence on the re-
action course (CuO is unable to dissolve in the reaction
medium). This is ascribed to the easy oxidation of the metal
or of CuI to CuII by atmospheric oxygen in the presence of
both the base and nitro compound. In fact, no significant ox-
idation is observed in the presence of only one reagent: they
are both required, the nitro compound providing the acidity
and the amine bringing the salt in solution. An experiment
with both the reagents and copper powder under an argon
atmosphere showed a negligible reaction progress. The
anion moderately affects the conversion attained after 40 h;
however, in early reaction stages, a significant influence on
the induction period has been observed (see further discus-
sions, Figure 2).
The catalytic effect of copper(II) on the condensation of
primary nitro compounds with dipolarophiles has been evi-
denced by plotting the observed percentage conversion of
dipolarophile into product versus time for two model reac-
tions: 1) ethyl nitroacetate (1e) with styrene (3) (Figure 1)
and 2) nitropentane (1c) with methyl acrylate (6) (Figure 2).
The graphs refer to different catalytic systems, affecting
both the reaction rate (slope) and the induction period.
Thus, Figure 1 shows the progress of the reaction of ethyl ni-
troacetate and styrene with four catalytic systems:
1) DABCO/copper powder, 2) DABCO/copper(II) triflate,
Figure 2. Conversion plots versus time for the condensation of nitropen-
tane (1c) and methyl acrylate (6). At the top: conversion plots in absence
~
of copper (e, ), in presence of 5 mol% of copper(II) triflate (h, &), cop-
&
*
per(II) acetate (g, ) and copper (f, ). The markers indicate the times at
which samples were taken and the lines merely serve as a guide to the
eye. At the bottom: enlarged early stages. See the Experimental Section
for details.
3) DABCO/copper(II) acetate and 4) DABCO alone (Fig-
ure 1a–d, respectively). Initial reaction rates decrease in the
order listed above and are attained after induction periods
of a few minutes for (a), about 0.5 h for (b) and (c) and 24h
for (d). These are better appreciated in the bottom graph of
Figure 1, in which the early reaction stages are shown on an
enlarged time scale.
The long induction period observed in the absence of
copper can be explained by the reaction sequence reported
in Scheme 1.[29] Since formation of the H-bonded salt A is
very fast, the induction time observed in this reaction
(Figure 1) appears to be required for the intermediate cyclo-
Figure 1. Conversion plots versus time for the condensation of ethyl ni-
troacetate (1e) and styrene (3). At the top: conversion plots in the ab-
~
*
sence of copper (d, ), in presence of 5 mol% of copper (a, ), copper-
&
A
times at which the samples were taken and the lines merely serve as a
guide to the eye. At the bottom: enlarged early stages. See the Experi-
mental Section for details.
Scheme 1. Mechanism for the DABCO-catalysed condensation of ethyl
nitroacetate and styrene.
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Chem. Eur. J. 2008, 14, 7903 – 7912

Synthesis of 4,5-Dihydroisoxazoles
FULL PAPER
Table 5. Reactions of nitro compounds 1a–f with various alkenes 2–8 in
adduct B to reach a steady concentration before the rate-de-
termining dehydration step to 13 attains its maximum rate.
When CuII is present in the catalytic system, we might
assume an analogous reaction sequence with copper(II) co-
ordination replacing the H-bond. The presence of CuII in
the catalytic system causes an increase of the maximum re-
action rate and a dramatic drop of the induction period. The
lack of induction time observed when Cu0 is employed (only
a few minutes are needed for the metal to get oxidised, Fig-
ure 1a) suggests that copper(II) chelate salts of ethyl nitro-
the presence of a copper/base catalytic system.[a]
ACHTREUNG
acetate are the reacting species.[34] The reaction rate (slope)
R3
R4
R5
Product
Yield [%][b]
is greatly enhanced (almost 50% conversion in 90 min): cy-
cloaddition might become the rate-determining step without
significant equilibration, water release being faster. When
copper is supplied as the triflate (Figure 1b) or acetate (Fig-
ure 1c), the observed induction time (about 1 h in both
cases) is possibly required for the anions to attain equilibri-
um in CuII coordination, thus affecting both the cycloaddi-
tion step (induction time) and the loss of water (reaction
rate). Owing to the higher stability of the CuII chelate salt of
ethyl nitroacetate relative to triflate and acetate, the differ-
ence between these salts is barely detected (Figure 1b,c).
As already pointed out, nitroalkanes do not condense
with dipolarophiles in the presence of the base alone. Thus,
the model reaction of 1-nitropentane with methyl acrylate,
in the presence of NMP or of DABCO does not give any cy-
cloadduct after 40 h (Figure 2e). If copper powder
(0.05 equiv) is added to the reaction mixture, the reaction
begins after about 4h, as shown by the plot of the percent-
age conversion versus time (Figure 2f). The induction time
might reasonably be ascribed to the oxidation of Cu0, which
is much slower with nitropentane than with nitroacetate,
due to the difference in acid strength and in salt stability.
However, the same reaction, on addition of 0.05 equivalents
of nitroacetate (1e) to 1-nitropentane (1c, 1 equiv) showed
no significant change in the induction period.
The other graphs, referred to different copper(II) salts,
show induction times varying with the anion and reasonably
depending on the equilibria preceding the rate-determining
step. Moreover, CuII might be coordinated to the dipolaro-
phile too. In fact, poorer results are obtained from reactions
of nitropentane with sluggish dipolarophiles that are unable
to coordinate with CuII (Table 5, entries 4, 7, and 11).
The catalytic effect of CuII on additions of nitronates[35,36]
or of silyl nitronates[37] is well documented. In the present
condensation, there is evidence that coordination with CuII
catalyses the cycloaddition step and the loss of water as
well.[38]
Entry
1
2
3
Me
nBu
EtOCO
nBu
EtOCO
MeO2C
nBu
Me
9
90
99
99
61
97
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
4[c]
5
H
H
H
À
Ph
Ph
Ph
6[c]
7[c]
8
G
74
17, 27[d]
89
À
CH2CH2CH2
CO2Me
CO2Me
CO2Me
OEt
H
H
H
H
H
H
H
H
H
9
Et
87
93
62
90
95
80
95
99
10
11
12
13
14[c]
15
16
nBu
nBu
nBu
EtOCO
nBu
CONMe2
CH2OH
CH2OH
Ph
PhCO
PhCO
CONMe2
[a] Reaction conditions: nitro compound (1.06 mmol), alkene
(0.424 mmol), NMP (0.084–0.212 mmol), copper or copper(II) acetate
(5 mol% with respect to the alkene), CHCl3 (1.4mL). See the Experi-
mental Section for details. [b] Isolated yield, determined on the analyti-
cally pure product and based on the dipolarophile. [c] Copper or copper-
AHCTRE(UNG II) acetate, 10 mol% with respect to the alkene. [d] The reaction was
carried out at 808C.
larophile, such as styrene, differences, in terms of yield, have
been found between activated and non-activated nitro com-
pounds: ethyl nitroacetate (1e) (entry 5, 97%) gives a
higher yield than 1-nitropentane (1c) (entry 4, 61%) or
methyl 4-nitrobutanoate (1d) (entry 6, 74%). The same be-
haviour is observed with allyl alcohol (8) (95 vs. 80%, en-
tries 13 and 14, respectively). Nitroalkanes show similar re-
sults (entries 8, 9 and 10) in reactions with the acrylate 6: a
better yield is obtained with nitropentane than with nitro-
ethane as a result of extensive decomposition of the latter.
Cyclopentene (5) with nitropentane gives the cycloadduct 15
in poor yield. (entry 7, 17%) even forcing the reaction con-
ditions (808C, 27%). It is worth noting that when a free hy-
droxy group is present in the dipolarophile neither catalyst
deactivation nor side reactions of the alcohol are observed
(entries 13 and 14). This outcome allows the incorporated
unprotected hydroxy group to function as handle for further
synthetic elaborations. The observed reactivities qualitative-
ly accord with the reactivity sequences reported for benzoni-
trile oxide and for N-methyl-C-phenyl nitrone towards dif-
ferent olefins: in fact, cyclopentene corresponds to very low
reactivity values.[40] This agreement supports the analogy of
these 1,3-dipoles with the nitronate, involved in the cycload-
dition depicted in Scheme 1. As a copper source for the cat-
Synthetic applications: With optimised conditions in hand,
the substrate scope and limits of the reaction were explored
by using a broad spectrum of alkenes with different struc-
tures and electronic demands as well as various nitro com-
pounds (Table 5).
With a reactive dipolarophile, such as norbornene, the
yields of isoxazolines from activated and non-activated nitro
compounds (Table 5, entries 1–3). With a less-reactive dipo-
Chem. Eur. J. 2008, 14, 7903 – 7912
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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7907

F. Machetti, F. De Sarlo, and L. Cecchi
tive pressure of air; Rf values refer to TLC (visualised with UV light, per-
manganate or anisaldehyde stain) carried out on 25 mm silica-gel plates
(Merck F254), with the same eluent indicated for the column chromatog-
raphy. For gradient column chromatography, Rf values refer to the more
polar eluent. Solvent removal was performed by evaporation on a rota-
alytic system, either copper(II) acetate or copper metal (as
powder or wire)[39] can be used. The latter are especially
practical (a small piece of copper metal as a wire or turnings
is all that needs to be added to the reaction mixture) and
convenient for reactions involving oxygenated dipolaro-
philes.[41]
Finally, we scaled-up, as a representative process, the re-
action of ethyl nitroacetate (1e) with allyl alcohol (8)
[Eq. (3)].
1
vap at room temperature. H and 13C NMR spectra were recorded with a
Varian Mercuryplus 400 spectrometer (operating at 400 MHz for 1H and
1
100.58 MHz for 13C NMR) unless otherwise stated. The H NMR spectro-
scopic data are reported as (s=singlet, d=doublet, t=triplet, m=multip-
let or unresolved, br=broad signal, coupling constant(s) in Hz, integra-
tion). The multiplicities of the 13C NMR spectroscopic signals and assign-
ments were determined by means of gHSQC and gHMBC experiments.
Chemical shifts were determined relative to the residual solvent peak
(CHCl3: d=7.24for 1H and 77.0 ppm for 13C NMR spectra). EI (electron
impact) mass spectra (at an ionising voltage of 70 eV) were obtained by
using a Shimadzu QP5050A quadrupole-based mass spectrometer. Ion
mass/charge ratios (m/z) are reported as values in atomic mass units fol-
lowed by the intensities relative to the base peak in parenthesis. IR spec-
tra were recorded with a Perkin–Elmer 881 spectrophotometer. Elemen-
tal analyses were obtained by using an Elemental Analyser Perkin–
Elmer 240C apparatus. All compounds were named with Autonom (Beil-
stein Information Systems) and modified where appropriate.
For the sake of practicality, copper wire was used. In pre-
liminary experiments, copper wire was added to the mixture
of other reagents, then removed when the solution turned
pale green, in order to limit over dissolution of the metal.
However, considering that the amount of dissolved copper
is dependent on the amount of base, if we use only
2.5 mol% of base, the copper wire can be left as long as the
reaction is complete and partial decomposition of nitro ace-
tate is thus avoided. This operating procedure allows the
excess of the nitro acetate 1e to be lowered to 1.2 equiva-
lents relative to the dipolarophile. The reaction carried out
with 4mmol of dipolarophile proceeded with efficiency and
product 21 was isolated in 93% yield together with traces of
the corresponding 4-substituted regioisomer.
Materials: Commercially available (Lancaster or Aldrich) nitro com-
pounds (nitroethane, nitropropane, nitropentane, ethyl nitroacetate and
methyl 4-nitrobutanoate) and organic bases were used as supplied.
CHCl3 (ethanol free) was filtered through a short pad of potassium car-
bonate just before use. Allyl alcohol was distilled before use. Metal salts
of Rh, Cu, Ag, Ni, Pt and Pd were used without treatment. The copper
wire was freshly activated just before the use by rapid treatment with
20% aq. nitric acid, and was then washed and dried. Copper powder was
purchased from Fluka and used without further purification.
Determination of the catalytic activities of different metal salts (Table 1):
Various metal salts were screened in a homemade apparatus in which 6–8
reactions were carried out simultaneously in sealed tubes. The metal salt
(0.0212 mmol) was suspended in CHCl3 (1.4mL). Nitroethane ( 1a;
76 mL, 1.06 mmol), norbornene (2; 40 mg, 0.424 mmol) and DABCO
(24mg, 0.212 mmol) were added consecutively and the mixture heated at
608C. After 20 h, a portion was withdrawn, diluted in CDCl3 (0.6 mL)
1
and the H NMR spectrum was recorded (Varian Gemini 200 MHz). The
percentage conversion was evaluated by integrating the Norb-H proton
signal of the cycloadduct 9 (m, d=2.49 ppm) and the ethylenic protons
of norbornene (2) (s, d=5.90 ppm). Formation of cycloadduct 9 was as-
sumed to be the only process involving norbornene.
Conclusion
We have developed an efficient procedure based on a [Cu]/
NMP catalyst, which provides a route for the synthesis of
4,5-dihydroisozazoles from nitro compounds. This method is
the first general catalytic process of condensation between
nitro compounds and alkenes. The process uses a cheap and
commercially available catalyst, and does not require the ex-
clusion of oxygen or the use of meticulously dried solvents
to protect the catalytic system. New methodologies for the
facile synthesis of 4,5-dihydroisoxazoles enhance their at-
tractiveness as a platform for the synthesis of complex mole-
cules. The recognition that condensation between nitro com-
pounds and dipolarophiles can be promoted or accelerated
by a copper/base catalytic system offers unique mechanistic
insights with implications for the further development of
highly active and enantioselective catalysts. Studies are un-
derway to extend the applications of this reaction.
Reaction between nitroethane and norbornene in the presence of
DABCO/PdACHTER(UNG OAc)2: PdACHTRE(UGN OAc)2 (9.5 mg, 0.0425 mmol) was suspended in
CHCl3 (2.8 mL). Nitroethane (1a; 153 mL, 2.12 mmol), norbornene (2;
80 mg, 0.85 mmol) and DABCO (48 mg, 0.425 mmol) were added consec-
utively and the mixture heated at 608C for 20 h. The mixture was then
concentrated and the resulting residue showed a spot with the same Rf as
an authentic sample of 9 (hexane/diethyl ether 1:1, Rf =0.48). The residue
was then dissolved in diethyl ether (15 mL), washed with HCl 5% (3”
15 mL), brine (3”15 mL) and the organic layer dried (sodium sulphate).
The solvent was evaporated to afford 9 (8 mg, 12%) as a clear oil.
Determination of the activities of different base/copper(II) acetate cata-
lytic systems (Table 2): Various base/CuACHTRE(UNG OAc)2 catalytic systems were
screened by using the apparatus mentioned above. Copper(II) acetate
(3.9 mg, 0.0212 mmol) was suspended in CHCl3 (1.4mL). Nitroethane
(1a; 76 mL, 1.06 mmol), norbornene (2; 40 mg, 0.424 mmol) and the base
(0.212 mmol) were added consecutively and the mixture heated at 608C.
After 20 and 40 h, a portion was withdrawn, diluted in CDCl3 (0.6 mL)
1
and the H NMR spectrum recorded (Varian Gemini 200 MHz). The per-
centage conversion was evaluated by integrating the CHC=N or Norb-H
proton signal of the cycloadduct 9 (d, d=2.93 or 2.49 ppm, respectively)
and the ethylenic protons of norbornene (2) (s, d=5.90 ppm). Formation
of cycloadduct 9 was assumed to be the only process involving norbor-
nene.
ExperimentalSection
Generalmethods
:
Chromatographic separations were performed on
Optimisation of reaction conditions by varying the base/metalratio and
silica gel 60 (40–6.3 mm) with analytical grade solvents, driven by a posi-
dipolarophile concentration (Table 3): NMP/CuCAHTRE(UNG OAc)2 and DBU/Cu-
7908
www.chemeurj.org
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2008, 14, 7903 – 7912

Synthesis of 4,5-Dihydroisoxazoles
FULL PAPER
A
CH3), 2.32 (m, 1H; Norb-H), 2.49 (m, 1H; Norb-H), 2.93 (d, J=8.0 Hz,
1H; CHC=N), 4.39 ppm (d, J=8.0 Hz, 1H; CHON); 13C NMR: d=11.9
(q; CH3), 22.6 (t; Norb-C), 27.2 (t; Norb-C), 32.0 (t; Norb-C), 38.0 (d;
Norb-C), 42.8 (d; Norb-C), 60.6 (d; CC=N), 86.1 (d; CON), 155.4ppm (s,
C=N); IR (CDCl3): n˜ =2964, 2877, 1630, 1455, 1436, 1384, 1331 cmÀ1; MS
(EI): m/z (%): 151 (36) [M]+, 131 (10), 109 (8), 84(68), 67 (100); ele-
mental analysis calcd (%) for C9H13NO (151.21): C 71.49, H 8.67, N 9.26;
found: C 71.19, H 9.02, N 9.31.
ent concentrations of dipolarophile by using the same apparatus as
above. Copper(II) acetate (3.9 mg, 0.0212 mmol) was suspended in
CHCl3 (1.4or 0.7 mL). Nitroethane ( 1a; 76 mL, 1.06 mmol), norbornene
(2; 40 mg, 0.424 mmol) and the base (0.424, 0.212, 0.085, 0.0424 or
0.0212 mmol) were added consecutively and the mixture was heated at
608C. After 20 and 40 h, reaction mixtures were analysed as reported
above. The percentage conversion was evaluated as above (Table 2).
Isoxazoline 10 (5-butyl-3-oxa-4-azatricyclo[5.2.1.02,6]dec-4-ene): Nitropen-
tane (1c; 130 mL), norbornene (2; 40 mg), NMP (26 mL, 0.212 mmol) and
copper powder (1.3 mg, 0.0212 mmol) gave after 40 h and chromato-
graphic purification (hexane, then hexane/diethyl ether 10:1, Rf =0.26) 10
as a colourless oil (81 mg, 99%). 1H NMR: d=0.88 (t, J=14.0 Hz, 3H;
CH3), 0.99–1.24(m, 3H; C H2CH3, Norb-H), 1.24–1.43 (m, 3H; CH2C=N,
Norb-H), 1.42–1.61 (m, 4H; CH2C=N, Norb-H), 2.08–2.18 (m, 1H;
CH2CH2CH3), 2.24–2.38 (m, 2H; Norb-H, CH2CH2CH3), 2.44–2.48 (m,
1H; Norb-H), 2.95 (d, J=8.3 Hz, 1H; CHC=N), 4.35 ppm (d, J=8.3 Hz,
1H; CHON); 13C NMR: d=13.7 (q; CH3), 22.4(t; CH2CH3), 22.6 (t;
Norb-C), 26.3 (t; CH2C=N), 27.2 (t; Norb-C), 28.3 (t; CH2CH2CH3), 32.0
(t; Norb-C), 38.1 (d; Norb-C), 42.8 (d; Norb-C), 59.3 (d; CHC=N), 85.9
(d; CON), 158.8 ppm (s; C=N); IR (CDCl3): n˜ =2961, 2875, 1619,
1456 cmÀ1; MS (EI): m/z (%): 193 (13) [M]+, 178 (3), 164(30), 151 (100),
126 (22), 67 (54); elemental analysis calcd (%) for C12H19NO (193.29): C
74.57, H 9.91, N 7.25; found: C 74.27, H 10.28, N 7.07.
Influence of the copper source on the condensation of nitro compounds
with dipolarophiles (Table 4): Different copper sources (see Table 4)
were screened by using the same apparatus as before. A copper salt,
powder (0.0212 mmol) or a piece of copper wire was suspended in CHCl3
(1.4mL). Nitropentane ( 1c; 130 mL, 1.06 mmol), ethyl vinyl ether (4;
41 mL, 0.424 mmol,) and NMP (26 mL 0.212 mmol) were added consecu-
tively and the mixture heated at 608C. After 40 h, a portion was with-
drawn, diluted in CDCl3 (0.6 mL) and the 1H NMR spectrum recorded
(Varian Gemini 200 MHz). The percentage conversion was evaluated by
integrating the 5-H proton signal of the cycloadduct 19 (d, d=5.44 ppm)
and the ethylenic protons of ethyl vinyl ether (4) (dd, d=6.42 ppm). For-
mation of cycloadduct 19 was assumed to be the only process involving
ethyl vinyl ether.
Determination of dipolarophile conversion as a function of time for dif-
ferent catalytic systems (Figures 1 and 2): Various catalytic systems were
screened in the usual apparatus. The samples were analysed by using a
1H NMR spectroscopic technique.
Isoxazoline 11 (3-oxa-4-aza-tricyclo[5.2.1.02,6]dec-4-ene-5-carboxylic acid
ethylester) : Ethyl nitroacetate (1e; 118 mL), norbornene (2; 40 mg),
NMP (10 mL, 0.0845 mmol) and CuACHTER(UNG OAc)2 (3.9 mg, 0.0212 mmol) gave
Preparation of samples (Figure 1): A mother reaction mixture was pre-
pared by dissolving ethyl nitroacetate (1e; 1.656 g, 2.5 equiv), styrene (3;
0.531 g, 1.0 equiv) and DABCO (0.114g, 0.2 equiv) in CHCl 3 (25.07 g) at
room temperature; then eight sample reactions were obtained by weigh-
ing 2.333 g of the mother mixture. Each sample was then heated at 608C
directly or after the addition of copper powder (1.4mg) or copper(II)
acetate (3.9 mg). Reactions were carried out simultaneously in sealed
tubes in the usual apparatus and screened at different times.
after 20 h and chromatographic purification (hexane then hexane/diethyl
ether 3:1, Rf =0.25) 11 as a clear oil (88 mg, 99%). Elemental analysis
calcd (%) for C11H15NO3 (209.2): C 63.14, H 7.23, N 6.69; found: C 62.94,
H 7.41, N 7.07; the spectral data are identical to those previously report-
ed.[28]
Isoxazoline 12 (3-butyl-5-phenyl-4,5-dihydroisoxazole): Nitropentane (1c;
130 mL), styrene (3; 4 9mL), NMP (26 mL, 0.212 mmol) and CuACHTREUNG(AcO)2
Conversion evaluation: An aliquot portion (80 mL) was diluted with
CDCl3 (0.6 mL). After addition of [D6]DMSO (ꢀ30 mL) and trifluoro-
(7.7 mg, 0.0424 mmol) gave after 40 h and chromatographic purification
(hexane, then hexane/diethyl ether 3:1, Rf =0.29) 12 as a colourless liquid
(53 mg, 61%). 1H NMR: d=0.91 (t, J=7.4Hz, 3H; C H3), 1.30–1.40 (m,
2H; CH2CH3), 1.50–1.58 (m, 2H; CH2CH2CH3), 2.36 (t, J=7.8 Hz, 2H;
CH2C-3), 2.87 (dd, J=8.0, 17.0 Hz, 1H; 4-H), 3.33 (dd, J=10.8, 17.0 Hz,
1H; 4-H), 5.13 (dd, J=8.0, 10.8 Hz, 1H; 5-H), 7.12–7.18 ppm (m, 5H;
Ph-H); 13C NMR: d=13.6 (q; CH3), 22.3 (t; CH2CH3), 27.3 (t; CH2C-3),
28.4( CH2CH2CH3), 45.3 (t; C-4), 81.1 (d; C-5), 125.6 (d, 2C; Ph-C) 127.9
(d; Ph-C), 128.6 (d, 2C; Ph-C), 141.3 (s; Ph-C), 158.5 ppm (s; C-3); IR
1
acetic acid (ꢀ4 mL) the H NMR spectrum was recorded (Varian Gemini
200 MHz) and the percentage conversion was evaluated by integrating
the 4-H proton signal of the cycloadduct 13 (dd, d= ꢀ3.10 ppm), com-
bined with the signal of 5-H from cycloadduct 13 (dd, d= ꢀ5.7 ppm) and
the ethylenic protons of styrene (3) (m, d=5.55–5.70 ppm).
Preparation of samples (Figure 2): Nitropentane (1c; 1.493 g, 2.5 equiv),
methyl acrylate (6; 0.439 g, 1.0 equiv), NMP (0.31 g, 0.5 equiv) and
CHCl3 (25.07 g) were mixed at room temperature. Then, eight sample re-
actions were obtained by weighing 2.271 g of the above mother mixture,
which was treated as above.
(CDCl3): n˜ =2959, 2931, 1624, 1597, 1548, 1493, 1456, 1466, 1432 cmÀ1
MS (EI): m/z (%): 203 (6) [M]+, 161 (51), 144(27), 104(100); elemental
;
analysis calcd (%) for C13H17NO (203.28): C 76.81, H 8.43, N 6.89; found:
C 76.71, H 8.59, N 7.06.
Conversion evaluation: An aliquot portion (80 mL) was diluted with
CDCl3 (0.6 mL), the 1H NMR spectrum was recorded (Varian Gemini
200 MHz) and the percentage conversion was evaluated by integrating
the 5-H proton signal of the cycloadduct 18 (m, d= ꢀ4.98 ppm) and the
ethylenic protons of methyl acrylate (6) (m, d=5.76–5.88 ppm).
Isoxazoline 13 (ethyl 5-phenyl-4,5-dihydro-3-isoxazolecarboxylate): Ethyl
nitroacetate (1e; 118 mL), styrene (3; 4 9mL), NMP (10 mL, 0.0845 mmol)
and copper powder (1.3 mg, 0.0212 mmol) gave after 20 h and chromato-
graphic purification 13 (hexane/diethyl ether 2:1, Rf =0.26) as a colour-
less oil. Before chromatographic purification the crude material was dis-
solved in diethyl ether (15 mL) and saturated NaCO3 (15 mL) was added.
The mixture was vigorously stirred for 30 min and then the organic layer
was washed with brine (3”15 mL), dried (sodium sulphate) and concen-
trated under reduced pressure (90 mg, 97%). Elemental analysis calcd
(%) for C12H13NO3 (219.24): C 65.74, H 5.98, N 6.39; found: C 65.46, H
6.01, N 6.51; the spectral data are identical to those previously report-
ed.[28]
Generalprocedure for the preparation of isoxazoilnes 9–24 : Nitro com-
pound (1.06 mmol), dipolarophile (0.424 mmol) and NMP were added in
sequence to a suspension of either CuCAHTRE(UNG OAc)2 or copper powder in CHCl3
(1.4mL). The stirred mixture, which had been heated in a sealed tube at
608C (unless otherwise stated), turned light green and became clear after
10–20 min (less than 5 min for activated nitro compounds). Stirring was
then maintained for the indicated time. After this time, the solvent was
removed and the residue was dissolved in CH2Cl2 (10 mL); silica gel
(200 mg) was added to the mixture and the solvent evaporated. The silica
gel with the adsorbed product was loaded onto the top of a column of
silica gel and purified by chromatography with the indicated eluent.
Isoxazoline 14 (methyl 3-(5-phenyl-4,5-dihydro-3-isoxazolyl)propanoate):
Methyl 4-nitrobutanoate (1d; 136 mL), styrene (3; 4 9mL), NMP (26 mL,
0.212 mmol) and copper powder (1.3 mg, 0.0212 mmol) gave after 112 h
and chromatographic purification (hexane, then hexane/diethyl ether 2:3,
Rf =0.27) 14 as a yellow oil (73 mg, 74%). 1H NMR: d=2.60–2.72 (m,
4H; CH2CH2CO, CH2CH2CO), 2.90 (dd, J=17.0, 8.0 Hz, 1H; 4-H), 3.36
(dd, J=17.0, 10.8 Hz, 1H; 4-H), 3.67 (s, 3H; OCH3), 5.53 (dd, J=8.0,
10.8 Hz, 1H; 5-H), 7.26–7.38 ppm (m, 5H; Ph-H); 13C NMR: d=23.2 (t;
CH2CH2C=O), 30.4(t; CH2CH2C=O), 45.7 (t; C-4), 51.8 (q; OCH3), 81.6
Isoxazoline
9
(5-methyl-3-oxa-4-azatricyclo[5.2.1.02,6]dec-4-ene): Nitro-
ethane (1a; 76 mL), norbornene (2; 40 mg), NMP (26 mL, 0.212 mmol)
and copper powder (1.3 mg, 0.0212 mmol) gave after 20 h and chromato-
graphic purification (hexane/diethyl ether 2:1, Rf =0.25) 9 as a clear oil,
which turned to clear pale yellow on standing (58 mg, 90%). 1H NMR:
d=1.00–1.22 (m, 3H; Norb-H), 1.38–1.58 (m, 3H; Norb-H), 1.88 (s, 3H;
Chem. Eur. J. 2008, 14, 7903 – 7912
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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7909

F. Machetti, F. De Sarlo, and L. Cecchi
(d; C-5), 125.7 (d, 2C; Ph-C), 128.0 (d; Ph-C), 128.6 (d, 2C; Ph-C), 141.0
(s; Ph-C), 156.9 (s; C-3), 172.7 ppm (s; C=O); IR (CDCl3): n˜ =3032,
(%) for C9H15NO3 (185.22): C 58.36, H 8.16, 4, N 7.56; found: C 57.98, H
8.33, N 7.68; the spectral data are identical to those previously report-
ed.[33]
2954, 2840, 1733 (C=O), 1623, 1603, 1552, 1494, 1438, 1366, 1339 cmÀ1
;
MS (EI): m/z (%): 233 (51) [M]+, 232 (28), 202 (39) [MÀOMe]+, 200
Isoxazoline 19 (3-butyl-5-ethoxy-4,5-dihydroisoxazole): Four preparations
were carried out by using identical reaction conditions but with different
catalytic systems.
+
(37), 174(12) [ MÀCO2Me]+, 156 (51), 104(100), 91 (20), 77 (33) [Ph]
;
elemental analysis calcd (%) for C13H15NO3 (233.26): C 66.94, H 6.48, N
6.00; found: C 66.64, H 6.77, N 6.04.
Isoxazoline 15 (3-butyl-4,5,6,6a-tetrahydro-3aH-cyclopenta[d]isoxazole)
1) A sealed tube was charged with Cu
suspended in CHCl3 (1.4mL). Nitropentane ( 1c; 130 mL, 1.06 mmol),
ethyl vinyl ether (4; m1L 0.424 mmol) and NMP (26 mL,
ACHTRE(UNG AcO)2 (3.9 mg, 0.0212 mmol)
Experiment conducted with copper acetate at 608C: A sealed tube was
charged with copper(II) acetate (7.7 mg, 0.0424 mmol) suspended in
CHCl3 (1.4mL). Nitropentane ( 1c; 130 mL, 1.06 mmol), cyclopentene (5;
37.5 mL, 0.424 mmol) and NMP (52 mL, 0.424 mmol) were then added
consecutively and the mixture heated at 608C. The solution was left stir-
ring for 40 h. After this time, the solvent was removed and the residue
dissolved in CH2Cl2 (10 mL); silica gel (200 mg) was added to the mix-
ture and the solvent evaporated. The silica gel with the adsorbed product
was loaded onto the top of a column of silica gel and purified by chroma-
tography (hexane, then hexane/diethyl ether 4:1, Rf =0.25) to provide the
product 15 as a clear pale-yellow oil (12 mg, 17%).
4
0.212 mmol) were then added consecutively and the mixture was
heated at 608C. The resulting solution was left stirring for 40 h. The
solvent was then removed and the residue dissolved in CH2Cl2
(10 mL). Silica gel (200 mg) was added to the mixture and the solvent
evaporated. The silica gel with the adsorbed product was loaded onto
the top of a column of silica gel and purified by chromatography
(hexane then hexane/diethyl ether 10:1, Rf =0.15) to give the product
19 as a clear oil, which turned yellow on standing (41 mg, 56%).
2) The reaction was repeated by using 1-ethylpiperidine instead of
NMP to give 38 mg of 19 (52%).
Experiment conducted with copper powder at 808C: A sealed tube was
charged with copper powder (2.7 mg, 0.0424 mmol) suspended in CHCl3
(1.4mL). Nitropentane ( 1c; 130 mL, 1.06 mmol), cyclopentene (5;
37.5 mL, 0.424 mmol) and NMP (52 mL, 0.424 mmol) were then added
consecutively and the mixture heated at 808C. The clear solution was left
stirring for 60 h. After this time, the solvent was removed and the residue
purified as above to give the product 15 as a clear pale-yellow oil (19 mg,
27%). 1H NMR: d=0.90 (t, J=7.4Hz, 3H; C H3), 1.16–1.22 (m, 2H;
CH2CH3), 1.23–1.70 (m, 6H; Bu-H, Cp-H), 1.79–1.84(m, 1H; Cp- H),
2.00–2.08 (m, 1H; Cp-H), 2.10–2.20 (m, 1H; CH2C=N), 2.30–2.40 (m,
1H; CH2C=N), 3.52 (t, J=7.8 Hz, 1H; CHC=N), 4.97 ppm (dd, J=5.0,
8.8 Hz, 1H; CHCON); 13C NMR: d=13.7 (q; CH3), 22.4(t; CH2CH3),
23.3, (t; Cp-C), 26.1 (t; CH2C=N), 28.4, (t; CH2CH2CH3), 30.2 (t; Cp-C),
35.9 (t; Cp-C), 54.3 (d; CC=N), 85.4(d; CON), 159.9 ppm (s; C=N); IR
(CDCl3): n˜ =2959, 2872, 1620, 1548, 1466, 1435 cmÀ1; MS (EI): m/z (%):
167 (6) [M]+, 152 (2) [MÀMe]+, 138 (22) [MÀEt]+, 125 (100), 108 (16),
93 (40); elemental analysis calcd (%) for C10H17NO (167.25): C 71.81, H
10.24, N 8.37; found: C 71.91, H 10.42, N 8.20.
3)
A
sealed tube was charged with copper powder (1.3 mg,
0.0212 mmol) suspended in CHCl3 (1.4mL). Nitropentane ( 1c;
130 mL, 1.06 mmol), ethyl vinyl ether (4; 4 1mL, 0.424 mmol) and
NMP (26 mL, 0.212 mmol) were then added consecutively and the
mixture heated at 608C. The resulting solution was left stirring for
40 h, then worked-up as for 1 to give the product 19 as a clear oil,
which turned yellow on standing (45 mg, 62%).
4) The reaction was repeated by using 1-ethylpiperidine instead of
NMP to give 19 (43 mg, 59%). 1H NMR: d=0.89 (t, J=7.4Hz, 3H;
CH3), 1.16 (t, J=7.2 Hz, 3H; OCH2CH3), 1.32–1.40 (m, 2H;
CH2CH3), 1.48–1.59 (m, 2H; CH2CH2CH3), 2.32–2.38 (m, 2H; CH2C-
3), 2.70 (dd, J=1.6, 7.6 Hz, 1H; 4-H), 2.96 (dd, J=6.6, 17.6 Hz, 1H;
4-H), 3.46–3.54 (m, 1H; OCH2CH3), 3.77–3.85 (m, 1H; OCH2CH3),
5.44 ppm (dd, J=1.6, 6.6 Hz, 1H; 5-H); 13C NMR: d=13.6 (q; CH3),
15.0 (q; OCH2CH3), 22.3 (t; CH2CH3), 27.3 (t; CH2C-3), 28.4(t;
CH2CH2CH3), 43.7 (t; C-4), 63.4 (t; OCH2), 101.9 (d; C-5),
159.4ppm (s; C-3); IR (CDCl 3): n˜ =2960, 2932, 1620, 1457 cmÀ1; MS
(EI): m/z (%): 171 (<1) [M]+, 156 (1) [MÀMe]+, 142 (7) [MÀEt]+,
129 (87), 126 (9) [MÀOEt]+, 97 (44), 72 (62), 57 (100); elemental
analysis calcd (%) for C9H17NO2 (171.238): C 63.13, H 10.01, N 8.18;
found: C 62.97, H 9.94, N 8.05.
Isoxazoline 16 (methyl 3-methyl-4,5-dihydro-5-isoxazolecarboxylate): Ni-
troethane (1a; 76 mL), methyl acrylate (6) (39 mL), NMP (26 mL,
0.212 mmol) and CuACHTREUNG(AcO)2 (3.9 mg, 0.0212 mmol) gave after 40 h and
chromatographic purification (hexane, then hexane/diethyl ether 1:2, Rf =
0.24) 16 as pale-yellow oil (54mg, 89%). 1H NMR: d=1.98 (m, 3H;
CH3), 3.19 (dm (doublet of multiplets), J=8.0 Hz, 2H; 4-H), 3.75 (s, 3H;
OCH3), 4.96 ppm (dd, J=8.0, 9.8 Hz, 1H; 5-H); 13C NMR: d=12.6 (q;
CH3), 42.4 (t; C-4), 52.7 (q; OCH3), 77.04(d; C-5), 15.48 (s; C-3),
170.9 ppm (s; C=O); IR (CDCl3): n˜ =2956, 2925, 2850, 1741 (C=O), 1633,
1551, 1437, 1386, 1325 cmÀ1; MS (EI): m/z (%): 143 (2) [M]+, 112 (2)
[MÀOMe]+ 84(72) [ MÀCO2Me]+, 56 (100); elemental analysis calcd
(%) for C6H9NO3 (143.14): C 50.35, H 6.34, N 9.79; found: C 50.16, H
6.60, N 10.05.
Isoxazoline 20 (3-butyl-4,5-dihydroisoxazole-5-carboxylic acid dimethyl-
AHCTREUNG
AHCTREUNG
after 20 h and chromatographic purification (hexane, then hexane/diethyl
ether 1:10, Rf =0.25) 20 as a colourless oil, which turned pale-yellow on
1
standing (76 mg, 90%). H NMR: d=0.87 (t, J=7.6 Hz, 3H; CH3), 1.26–
1.36 (m, 2H; CH2CH2CH3), 1.48–1.56 (m, 2H; CH2CH2CH3), 2.31 (t, J=
7.6 Hz, 2H; CH2C-3), 2.90 (dd, J=10.9, 17.0 Hz, 1H; 4-H), 2.94 (s, 3H;
NCH3), 3.11 (s, 3H; NCH3), 3.67 (dd, J=7.2, 17.0 Hz, 1H; 4-H),
5.12 ppm (dd, J=7.2, 10.9 Hz, 1H; 5-H); 13C NMR: d=13.6 (q; CH3),
22.2 (t; CH2CH3), 26.9 (t; CH2C-3), 28.2 (t; CH2CH2CH3), 35.9 (q;
NCH3), 37.1 (q; NCH3), 38.9 (t; C-4), 76.6 (d; C-5), 158.5 (s; C-3),
167.7 ppm (s; C=O); IR (CDCl3): n˜ =2960, 2933, 2874, 1649 (C=O), 1602,
1499, 1417, 1404 cmÀ1; MS (EI): m/z (%) 198 (4) [M]+, 181 (3), 168 (4),
167 (20), 126 (77), [MÀCONMe2]+, 72 (100); elemental analysis calcd
(%) for C10H18N2O2 (198.26): C 60.58, H 9.15, N 14.13; found: C 60.49, H
9.45, N 13.93.
Isoxazoline 17 (methyl 3-ethyl-4,5-dihydro-5-isoxazolecarboxylate): Ni-
tropropane (1b; 94 mL, 1.06 mmol), methyl acrylate (6; 39 mL), NMP
(26 mL, 0.212 mmol) and CuACHTRE(UGN AcO)2 (3.9 mg, 0.0212 mmol) gave after 40 h
and chromatographic purification (hexane then hexane/diethyl ether 5:3,
Rf =0.15) 17 as a pale-yellow oil (58 mg; 87%). 1H NMR: d=1.14(t, J=
9.2 Hz, 3H; CH3), 2.35 (q, J=9.2 Hz, 2H; CH2CH3), 3.19 (d, J=9.6 Hz,
2H; 4-H), 3.75 (s, 3H; OCH3), 4.94 ppm (t, J=9. 6 Hz, 1H; 5-H);
13C NMR: d=10.7 (q; CH3), 20.8 (t; CH2CH3), 40.8 (t; C-4), 52.6 (q;
OCH3), 76.8 (d; C-5), 159.4(s; C-3), 171.0 ppm (s; C=O); IR (CDCl3):
n˜ =2979, 2955, 1739 (C=O), 1626, 1602, 1461, 1438 cmÀ1; MS (EI): m/z
(%): 157 (2) [M]+, 140 (2), 126 (1) [MÀOMe]+, 98 (84) [MÀCO2Me]+,
70 (100); elemental analysis calcd (%) for C7H11NO3 (157.17): C 53.50, H
7.05, N 8.91; found: C 53.88, H 7.13, N 8.53.
Isoxazoline 21 (5-hydroxymethyl-4,5-dihydroisoxazole-3-carboxylic acid
ethylester) : Ethyl nitroacetate (1e); 118 mL), allyl alcohol (8; 29 mL),
NMP (10 mL, 0.0845 mmol) and copper powder (1.3 mg, 0.0212 mmol)
gave after 16 h and chromatographic purification (hexane, then hexane/
diethyl ether 1:4, Rf =0.24) 21 as a clear viscous liquid (70 mg, 95%). El-
emental analysis calcd (%) for C7H11NO4 (173.17): C 48.55, H 6.40, N
8.09; found: C 48.81, H 6.47, N 8.39; the spectral data are identical to
those previously reported.[29]
Isoxazoline 18 (methyl 3-butyl-4,5-dihydro-5-isoxazolecarboxylate): Ni-
tropentane (1c; 130 mL), methyl acrylate (6; 39 mL), NMP (26 mL,
0.212 mmol) and copper powder (1.3 mg, 0.0212 mmol) gave after 40 h
and chromatographic purification (hexane, then hexane/diethyl ether 4:3,
Rf =0.22) 18 as a colourless oil (73 mg, 93%). Elemental analysis calcd
7910
www.chemeurj.org
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2008, 14, 7903 – 7912

Synthesis of 4,5-Dihydroisoxazoles
FULL PAPER
Isoxazoline 22 ((3-butyl-4,5-dihydroisoxazol-5-yl)methanol): Nitropen-
tane (1c; 130 mL), allyl alcohol (8; 29 mL), NMP (26 mL, 0.212 mmol) and
copper powder (1.3 mg, 0.0212 mmol) gave after 40 h and chromato-
graphic purification (hexane, then hexane/diethyl ether 1:6, Rf =0.28) 22
as a pale-yellow oil (54mg, 80%). 1H NMR: d=0.90 (t, J=7.2 Hz, 3H;
CH3), 1.29–1.40 (m, 2H; CH2CH2CH3), 1.48–1.56 (m, 2H; CH2CH2CH3),
2.05 (brs, 1H; OH), 2.31 (t, J=7.6 Hz, 2H; CH2C-3), 2.77–2.83 (m, 1H;
4-H), 2.90–2.97 (m, 1H; 4-H), 3.50–3.56 (m, 1H; CH2OH), 3.70–3.76 (m,
1H; CH2OH), 4.59–4.66 ppm (m, 1H; 5-H); 13C NMR: d=13.7 (q; CH3),
22.3 (t; CH2CH3), 27.3 (t; CH2C-3), 28.4(t; CH2CH2CH3), 38.4(d; C-4),
63.8 (t; CH2OH), 79.7 (t; C-5), 159.6 ppm (s; C-3); IR (CDCl3): n˜ =3590
(OH), 2958, 2931, 2873, 1622, 1456, 1434 cmÀ1; MS (EI): m/z (%): 157 (4)
[M]+, 126 (28) [MÀCH2OH]+, 115 (66), 69 (72), 57 (100); elemental
analysis calcd (%) for C8H15NO2 (157.21): C 61.12, H 9.62, N 8.91; found:
C 61.04, H 9.29, N 9.22.
[1] a) Synthetic Applications of 1,3-Dipolar Cycloaddition Chemistry
Toward Heterocycles and Natural Products (Eds.: A. Padwa, W. H.
Pearson), Wiley, New Jersey, 2003; b) 1,3-Dipolar Cycloaddition
Chemistry (Ed.: A. Padwa), Wiley, New York, 1984.
[2] a) D. Giomi, F. M. Cordero, F. Machetti in Comprehensive Heterocy-
clic Chemistry III (Eds.: A. Katritzky, C. Ramsden, E. Scriven, R.
Taylor), Elsevier 2008; b) V. Jäger, P. A. Colinas in ref. 1a), Chap-
ter 6; c) J. Mulzer, Organic Synthesis Highlights; VCH, Weinheim,
1991; d) K. B. G. Torssell, Nitrile Oxides, Nitrones and Nitronates in
Organic Synthesis, VCH, New York, 1988, Chapter 5; e) P. Caramel-
la, P. Grünanger, in ref. 1b), Chapter 3.
[3] Phenylisocyanate: T. Mukaiyama, T. Hoshino, J. Am. Chem. Soc.
1960, 82, 5339–5342.
[4] For selected recent applications of phenylisocyanate see: a) K. N.
Fleming, R. E. Taylor, Angew. Chem. 2004, 116, 1760–1762; Angew.
Chem. Int. Ed. 2004, 43, 1728–1730; b) T. Rosenau, C. Adelwçhrer,
A. Hofinger, K. Mereiter, P. Kosma, Eur. J. Org. Chem. 2004, 1323–
1329; c) M. Prakesch, D. GrØe, R. GrØe, J. Carter, I. Washington,
K. N. Houk, Chem. Eur. J. 2003, 9, 5664–5672; d) K.-H. Park, M. M.
Olmstead, M. J. Kurth, Synlett 2003, 1267–1270; e) E. V. Koroleva,
Ya. M. Katok, T. V. Chernikova and F. A. Lakhvich, Chem. Hetero-
cycl. Compd. 2003, 39, 918–924; Khim. Geterotsikl. Soedin. 2003, 7,
1060–1066; f) F. S. Pashkovskii, Ya. M. Katok, E. M. Shchukina,
E. V. Koroleva, F. A. Lakhvich, Russ. J. Org. Chem. 2006, 42, 230–
237; Zh. Org. Khim. 2006, 42, 246–253; g) A. Kadowaki, Y. Nagata,
H. Unob. A. Kamimura, Tetrahedron Lett. 2007, 48, 1823–1825;
h) E. V. Koroleva, Y. M. Katok, F. A. Lakhvich, Natsyyanal’nai Aka-
demii Navuk Belarusi, Seryya Khimichnykh Navuk 2000, 3, 70–74;
Chem. Abstr. 2000, 134, 131337; i) J. Siu, I. R. Baxendale, R. A.
Lewthwaite, S. V. Ley, Org. Biomol. Chem. 2005, 3, 3140–3160; j) R.
Clayton, C. A. Ramsden, Synthesis 2005, 2695–2700.
Isoxazoline 23 (phenyl (5-phenyl-4,5-dihydroisoxazol-3-yl)methanone):
Benzoylnitromethane (1 f; 175 mg), styrene (8; (4 9mL), NMP (10 mL,
0.0845 mmol) and copper powder (1.3 mg, 0.0212 mmol) gave after 40 h
and chromatographic purification (hexane, then hexane/diethyl ether
10:1, Rf =0.24) 23 as a colourless oil (101 mg, 95%). Elemental analysis
calcd (%) for C16H13NO2 (251.28): C 76.48, H 5.21, N 5.57; found: C
76.07, H 4.90, N 5.87; the spectral data are identical to those previously
reported.[27]
Isoxazoline 24 (3-benzoyl-4,5-dihydroisoxazole-5-carboxylic acid dime-
thylamide): Benzoylnitromethane (1 f; 175 mg), dimethyl acryl amide (7;
44 mL), NMP (10 mL, 0.0845 mmol) and copper powder (1.3 mg) gave
after 20 h and chromatographic purification (petroleum ether, then petro-
leum ether/ethyl acetate 1:1, Rf =0.24) 24 as a pale-yellow oil (104mg,
99%). 1H NMR: d=3.00 (s, 3H; CH3), 3.18 (s, 3H; CH3), 3.44 (dd, J=
11.7, 17.8 Hz, 1H; 4-H), 4.06 (dd, J=7.6, 17.8 Hz, 1H; 4-H), 5.42 (dd, J=
7.6, 11.7 Hz, 1H; 5-H), 7.40–7.46 (m, 2H; Ph-Hmeta), 7.54–7.59 (m, 1H;
Ph-Hpara), 8.12–8.16 ppm (m, 2H; Ph-Hortho); 13C NMR: d=36.1 (q; CH3),
36.5 (t; C-4), 37.2 (q; CH3), 78.9 (d; C-5), 128.3 (d; 2C; Ph-Cmeta), 130.3
(d, 2C; Ph-Cortho), 133.6 (d; Ph-Cpara), 135.6 (s; Ph-Cipso), 157.9 (s; C-3),
[5] Tolylene 2,4-diisocyanate: M. G. Leslie-Smith, R. M. Paton, N.
Webb, Tetrahedron Lett. 1994, 35, 9251–9254.
[6] 1,4-Phenylene diisocyanate: V. Jäger, I. Müller, Tetrahedron 1985,
41, 3519–3528.
166.4(s; Me NC=O), 185.8 ppm (s; PhC=O); IR (CDCl3): n˜ =3064, 2940,
2
1658 (C=O), 1599, 1586 cmÀ1; MS (EI): m/z (%): 246 (<1) [M]+, 216 (2),
174(12) [ MÀCONMe2]+, 105 (100) [PhCO]+, 77 (52) [Ph]+, 72 (74); ele-
mental analysis calcd (%) for C13H14N2O3 (246.26): C 63.40, H 5.73, N
11.38; found: C 63.20, H 5.85, N 11.38.
[7] For recent selected examples that use 1,4-phenylene diisocyanate
see: a) M. Lemaire, N. Veny, T. Gefflaut, E. Gallienne, R. ChÞne-
vert, J. Bolte, Synlett 2002, 1359–1361; b) K. S.-L. Huang, E. H. Lee,
M. M. Olmstead, M. J. Kurth, J. Org. Chem. 2000, 65, 499–503.
[8] 4-Chlorophenyl isocyanate: A. P. Kozikowski, P. D. Stein, J. Am.
Chem. Soc. 1982, 104, 4023–4024.
[9] For selected recent applications of 4-chlorophenyl isocyanate see:
a) W. Itano, T. Ohshima, M. Shibasaki, Synlett 2006, 3053–3056;
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A. P. Kundu, A. Bhattacharjya, Tetrahedron 2005, 61, 2999–3012;
d) P. A. Wade, H. Le, N. V. Amin, J. Org. Chem. 2002, 67, 2859–
2863; e) J. Sengupta, R. Mukhopadhyay, A. Bhattacharjya, M. M.
Bhadbhade, G. V. Bhosekar, J. Org. Chem. 2005, 70, 8579–8582.
[10] Phosphorus oxychloride: a) G. B. Bachman, L. E. Strom, J. Org.
Chem. 1963, 28, 1150–1152; b) J. E. McMurry, Org. Synth. 1973, 53,
59–62.
Scale-up for the reaction between ethyl nitroacetate (1e) and allyl alco-
hol(8): Formation of isoxazoilne 21 : A sealed 50 mL schlenk tube con-
taining freshly activated copper wire was charged with allyl alcohol (8;
0.247 g, 4.24 mmol), ethyl nitroacetate (1e; 0.678 g, 5.08 mmol), NMP
(0.0105 g, 0.106 mmol) and CHCl3 (14mL), and the mixture was heated
at 608C. The resulting solution was left stirring for 46 h. After this time,
the solvent was removed and the residue dissolved in CH2Cl2 (50 mL).
Silica gel (2 g) was added to the mixture and the solvent evaporated. The
silica gel with the adsorbed product was loaded onto the top of a column
of silica gel and purified by chromatography (petroleum ether then dieth-
yl ether/petroleum ether 4:1, Rf =0.24) to give isoxazoline 21 (686 mg,
93%) as a viscous clear liquid containing as little as 3% of ethyl 4-(hy-
droxymethyl)-4,5-dihydro-3-isoxazolecarboxylate. Elemental analysis
calcd (%) for C7H11NO4 (173.17): C 48.55, H 6.40, N 8.09; found: C
48.15, H 6.37, N 8.35; the spectral data are identical to those previously
reported.[29]
[11] a) I. Akritopoulou-Zanze, V. Gracias, J. D. Moore, S. W. Djuric, Tet-
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[12] Acetyl chloride: a) E. Kaji, K. Harada, S. Zen, Chem. Pharm. Bull.
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Acknowledgements
The authors thank the Ministero dell’ Università e della Ricerca (MiUR,
Italy, project: COFIN-PRIN 2005 - prot. 2005038048) and the Università
di Firenze for financial support and for a postdoctoral fellowship (As-
segno di ricerca) to L.C. Financial support by the Ente Cassa di Rispar-
mio di Firenze for the purchase of the 400 NMR instrument is gratefully
acknowledged. B. Innocenti and M. Passaponti (Università di Firenze)
are acknowledged for technical support.
[15] Thionyl chloride Y.-J. Chen, C.-N. Li, J. Chin. Chem. Soc. 1993, 40,
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Chem. Eur. J. 2008, 14, 7903 – 7912
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
7911

F. Machetti, F. De Sarlo, and L. Cecchi
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[18] For other dehydrating agents see: a) N,N-diethylaminosulfur tri-
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[21] a) K. B. G. Torssell, O. Zeuthen, Acta Chem. Scand. B 1978, 32,
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Received: March 26, 2008
Published online: July 18, 2008
7912
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