Competitive Copper Catalysis in the Condensation of Primary Nitro Compounds with Terminal Alkynes: Synthesis of Isoxazoles

Article abstract of DOI:10.1002/ejoc.201600897

Isoxazoles, mainly 3,5-disubstituted, are prepared by catalytic condensation of primary nitro compounds with terminal acetylenes by using a copper/base catalytic system. The additional catalytic effect of the copper(II) salts is evidenced by comparing the kinetic profiles. Selectivity dependence on reaction conditions is considered for phenylacetylene in the following competitive processes: oxidative coupling of terminal alkynes to conjugated diynes catalyzed by Cu^IIand base in the presence of air; production of furazans beside condensation with benzoylnitromethane to 3-benzoylisoxazoles, as a result of the reaction of the dipolarophile with 3,4-dibenzoylfuroxan; addition of electron-poor alkynes (e.g., methyl propiolate) with themselves and with the nitro compound. Thus, oxidative coupling is negligible in reactions with “active” nitro compounds, whereas with nitroalkanes both products are observed: only trace amounts of isoxazoles are detected without copper. Similarly, in the presence of copper, 3-benzoyl-5-phenylisoxazole is predominant over the furazan. Furthermore, condensations of electron-poor alkynes give complex reaction mixtures in the presence of base alone, but cycloadducts are conveniently prepared with copper. The results indicate the practical and general utility of this catalytic method for synthetic practice.

Full text of DOI:10.1002/ejoc.201600897

DOI: 10.1002/ejoc.201600897
Full Paper
Synthetic Methods
Competitive Copper Catalysis in the Condensation of Primary
Nitro Compounds with Terminal Alkynes: Synthesis of
Isoxazoles
[a]
[b]
[b]
[a]
Ausilia Baglieri, Luca Meschisi, Francesco De Sarlo, and Fabrizio Machetti*
In memory of Paolina Bonari on the 100th anniversary of her birth
Abstract: Isoxazoles, mainly 3,5-disubstituted, are prepared by addition of electron-poor alkynes (e.g., methyl propiolate) with
catalytic condensation of primary nitro compounds with termi- themselves and with the nitro compound. Thus, oxidative cou-
nal acetylenes by using a copper/base catalytic system. The ad- pling is negligible in reactions with “active” nitro compounds,
ditional catalytic effect of the copper(II) salts is evidenced by whereas with nitroalkanes both products are observed: only
comparing the kinetic profiles. Selectivity dependence on reac- trace amounts of isoxazoles are detected without copper. Simi-
tion conditions is considered for phenylacetylene in the follow- larly, in the presence of copper, 3-benzoyl-5-phenylisoxazole is
ing competitive processes: oxidative coupling of terminal alk- predominant over the furazan. Furthermore, condensations of
II
ynes to conjugated diynes catalyzed by Cu and base in the electron-poor alkynes give complex reaction mixtures in the
presence of air; production of furazans beside condensation presence of base alone, but cycloadducts are conveniently pre-
with benzoylnitromethane to 3-benzoylisoxazoles, as a result pared with copper. The results indicate the practical and gen-
of the reaction of the dipolarophile with 3,4-dibenzoylfuroxan; eral utility of this catalytic method for synthetic practice.
Introduction
gents have been reported to serve the purpose.[18] Acylating
reagents are assumed to convert the nitro compounds into
acylated nitronic acids (or “mixed anhydrides”) and thence into
nitrile oxides, which undergo cycloaddition with the dipolaro-
Isoxazoles by Condensation of Alkynes with Nitro
Compounds
[
19–22]
phile [Equation (1)].
Isoxazoles are not only important building blocks and useful
synthons in synthetic organic chemistry,
[
1,2]
but they are also a
[
3]
significant motif in natural products, biologically active com-
[
4–6]
[7]
pounds,
investigational pharmaceutical compounds with
[
8–13]
wide application as drugs,
and advanced organic materi-
The physical properties and the construction of this
heterocyclic nucleus has attracted the interest of researchers
[
14]
als.
[
15,16]
for decades.
Among the numerous substrates utilized as
starting materials, primary nitro compounds combined with alk-
ynes have received wide attention, as the process builds up
[
17]
isoxazole derivatives directly. Acylating reagents (usually iso-
cyanates) in stoichiometric or excess amounts are used, in gen-
eral, for the condensation of primary nitro compounds with alk-
yne (likewise alkene) dipolarophiles, although various other rea-
Furoxans, the products of spontaneous dimerization of nitrile
[
23,24]
[
[
a] Istituto di chimica dei composti organometallici, c/o Dipartimento di
chimica Ugo Schiff, Consiglio nazionale delle ricerche (CNR),
Via della Lastruccia 13, 50019 Sesto Fiorentino, Firenze, Italy
E-mail: fabrizio.machetti@unifi.it
oxides,
are often detected in the above reactions, which
thus supports the role of nitrile oxides as reaction intermedi-
ates. Some authors have verified that in the absence of a di-
[
25–27]
polarophile furoxans are the main reaction products.
fabrizio.machetti@cnr.it
http://www.iccom.cnr.it/
http://www2.chim.unifi.it/
All these reactions, which use stoichiometric amounts of rea-
gents with unfavorable environmental impact, suffer from addi-
tional drawbacks: the formation of byproducts from either the
nitro compound or the dehydrating reagent complicates prod-
uct isolation and purification, which thus affects the yields.
b] Dipartimento di chimica Ugo Schiff, Università degli studi di Firenze,
Via della Lastruccia 13, 50019 Sesto Fiorentino, Firenze, Italy
Supporting information and ORCID(s) from the author(s) for this article are
available on the WWW under http://dx.doi.org/10.1002/ejoc.201600897.
Eur. J. Org. Chem. 0000, 0–0
1
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
Moreover several functional groups that would interact with to give the expected isoxazole derivatives in aqueous medium
the dehydrating reagent must be left out. Therefore, the above under pyridine or N-methylimidazole catalysis.[36] On the con-
reactions were considerably improved when we established trary, in dichloromethane solution with a catalytic amount of
that a catalytic amount of a suitable base was enough to pro- pyridine, similar reactions do not give the expected isoxazole
mote condensation of the alkynes (and alkenes) with “active” derivatives but isomeric products instead.[37] We already ob-
nitro compounds [those bearing an electron-withdrawing served the lack of catalytic activity of pyridine in chloroform
[
28]
group (EWG) geminal to the nitro group, including phenylnitro- solution in the condensation of benzoylnitromethane.
methane] and not with nitroalkanes [Equation (2)].
Con-
Con- densation of benzoylnitromethane with several alkynes has also
densations occur in chloroform as well as in hydroxylic solvents been reported to occur under poly(phosphoric acid) (PPA)/SiO2
[
28–31]
[38]
(
e.g., ethanol, water): in chloroform the catalytic effect[28] de- catalysis in refluxing toluene.
pends on the nature of the base, whereas in water, any base,
[
32]
either organic or inorganic, has the same catalytic effect. This
method avoids the use of excess amounts of highly polluting Results and Discussion
reagents and the formation of discarded products derived from
them; moreover, it tolerates many functional groups (e.g., OH,
Model Reactions
NH , etc.) that would interfere with most of the reagents that
were previously used in stoichiometric amounts. The above cat-
2
Copper-Catalyzed Condensation to Isoxazoles
alytic method has been referred to as the Machetti–De Sarlo The aim of this paper was to find an effective and selective
[
33–35]
reaction.
The solvent dependence of the base catalytic ef- catalytic system enabling the conversion of primary nitro com-
fect has been noticed by other authors. Indeed, condensation pounds and alkynes into isoxazoles. Catalyst composition and
of dimethyl acetylenedicarboxylate (DMAD) and similar esters reaction conditions were carefully investigated to establish fa-
with nitroacetates or benzoylnitromethane has been reported vorable selectivity towards condensation to the isoxazole for
Table 1. Reaction of nitro compounds 1a–h with various alkynes in the presence of a copper/base catalytic system.[a]
[
a] Reaction conditions: nitro compound (0.848–1.06 mmol), alkyne (0.424 mmol), NMP (20 mol-%), [Cu] (5 mol-%), unless otherwise indicated. [b] Yield of isolated
product after chromatography. [c] With a lower amount of base (10 mol-%) and [Cu] (5 mol-%). [d] Combined yield of the 4-H and 5-H isomers. [e] 4-H/5-H =
6:33. [f] With a lower amount of the catalyst: NMP (10 mol-%), [Cu] (2.5 mol-%). [g] NMP (100 mol-%). [h] TMEDA instead of NMP. See Table 3, entry 17.
6
Eur. J. Org. Chem. 0000, 0–0
www.eurjoc.org
2
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
each reagent pair. In fact, parallel competitive processes were obtained in the condensation of ethyl nitroacetate (1a) with 1-
found to interfere with this condensation: the addition of elec- octyne (ca. 80 % yield; Table 1, entry 2) favorably compares with
tron-poor alkynes (e.g., methyl propiolate) to themselves and the reported result obtained under PPA/SiO catalysis at higher
2
to the nitro compound; alkyne oxidative coupling, important temperature (50 % yield).[38] Notably, some functional groups
with sluggish reagents such as nitroalkanes; reaction of the di- did not interfere with the condensation (Table 1, entries 4–8).
polarophile with 3,4-dibenzoylfuroxan derived from benzoyl- The condensation of ethyl nitroacetate (1a) with methyl propi-
nitromethane, which leads to a furazan derivative. In analogy olate was successful only if interaction of the alkyne with the
with the established method for the condensation of nitro- base was avoided; otherwise, fast coupling of methyl propiolate
alkanes with alkene dipolarophiles, which requires the presence with itself gave the corresponding enyne dioate as the predom-
[
39,40]
[42,43]
of copper in the catalytic system,
the condensations of inant product.
nitro compounds with several terminal alkynes were performed
Therefore, by controlling the order of reagent addition, it was
II
under Cu and base catalysis in chloroform, and the results are possible to increase the conversion of methyl propiolate into
[
41]
collected in Table 1.
phenylacetylene (Table 1 entry 1) and propargyl alcohol NMP (Table 1, entry 9; 40 % overall yield of isomers 10a and
Table 1, entry 4) were compared to those previously reported 10′a), whereas the use of base alone, such as DABCO, gave a
The yields for the condensations of the cycloadducts. A better result was obtained by using copper/
(
II
[28–30]
without Cu salt,
but no remarkable differences were as- complex mixture containing a very low amount of the desired
certained. However, the kinetic profiles for the phenylacetylene
condensations (Figure 1) evidenced an additional catalytic ef-
II
fect that may have been due to the presence of the Cu salt.
In fact, the conversion of phenylacetylene into 3-carbethoxy-5-
II
phenylisoxazole (2a) was complete within 8 h with Cu and in
72 h with base alone.
Figure 1. Kinetic profiles for the condensation between ethyl nitroacetate (1a)
and phenylacetylene to isoxazole 2a (Table 1, entry 1). In chloroform, no
reaction was observed without a catalyst (solid triangles): percentage of the
dipolarophile with DABCO (white squares) or DABCO/[Cu] (solid squares) ca-
talysis. See the Experimental Section for details.
Either 1,4-diazabicyclo[2.2.2]octane (DABCO) or N-methyl-
piperidine (NMP) could be used in combination with the Cu salt
to catalyze the condensations of ethyl nitroacetate (1a); how-
ever, the catalytic system NMP + Cu salt was preferred, because
it could, in general, be applied with nitroalkanes (see below).
Some reactions reported in Table 1 were also performed with
metallic Cu (powder) without any significant differences; in fact,
the metal was rapidly oxidized by air in an excess amount of
Figure 2. Kinetic profiles for condensation between ethyl nitroacetate (1a)
and 1-(pyrrolidin-1-yl)prop-2-yn-1-one to mixtures of isoxazoles 11a and 11′
a (Table 1, entry 10). In chloroform, no reaction was observed without a
catalyst (solid circles): conversion of the dipolarophile with DABCO (white
squares) or DABCO/[Cu] (solid squares) catalysis (top); yield of isoxazoles 11a
and 11′a (mixture) with DABCO (white triangles) or DABCO/[Cu] (solid trian-
gles) catalysis (bottom). See the Experimental Section for details.
[
40]
the nitroacetate.
Nitroacetate Esters and Amides
Terminal alkynes selectively afforded the 5-substituted isox-
azole derivatives, as reported in Table 1, entries 1–8. The result
Eur. J. Org. Chem. 0000, 0–0
www.eurjoc.org
3
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
cycloadduct. Notably, the condensation was satisfactory if an Benzoylnitromethane
acetylenic amide was used (Table 1, entry 10; 73 % yield of 11a
along with a trace amount of 11′a). The kinetic profiles for the Benzoylnitromethane (1e) is known to give several products
conversions are illustrated in Figure 2 (top): no conversion was according to the reaction conditions, with or without dipolaro-
observed without a catalyst. The plot of yield versus time (Fig- phile implication. Those concerning benzoylnitromethane (1e)
ure 2, bottom) shows that the addition of copper to the base alone or with phenylacetylene are illustrated in Scheme 1.
not only reduced the induction time but also increased the
Benzoylnitromethane is easily hydrolyzed in the presence of
yield. Condensations of ethyl nitroacetate with monosubsti- base.[ Self-condensation occurs spontaneously with any sol-
tuted alkynes containing EWGs were not regioselective, as both vent and environmental conditions to furoxan 26, whereas di-
isomers were obtained and the 5-substituted isomers (i.e., 10a oxadiazine isomer 27 was reported to be produced with an
44]
[
45]
and 11a) predominated.
excess amount of nitrous acid.
A third isomer, isoxazole 28,
Nitroacetamides reacted readily with alkynes: amide 1c gave becomes the sole self-condensation product upon treatment
II
[46]
1
3c in good yield preferably with 10 mol-% of base (Table 1, with the catalytic system DABCO/Cu in chloroform.
In the
entry 12). In view of the possible use of these 3-carbamoylisox- presence of dipolarophiles, isoxazoline (from alkenes) or isox-
azole derivatives, the condensations of nitroacetamide 1d sub- azole (from alkynes, e.g., 16e) cycloadducts are the expected
stituted with a protected amino function were performed with products. However, furoxan 26 in turn reacts with dipolaro-
two alkynes (Table 1, entries 13 and 14). The quantitative HCl- philes, owing to its peculiar dipolar reactivity, and this leads to
mediated removal of the tert-butoxycarbonyl (Boc) protecting furazans (e.g., 29) upon hydrolytic loss of benzoic acid from the
group gave pendant amine units 24 and 25 as hydrochloride cycloadducts. This process was previously examined in detail for
[
47]
salts.
the reaction with norbornene as a dipolarophile. This picture
Scheme 1. Reactions of benzoylnitromethane alone or with phenylacetylene.
Table 2. Reaction of benzoylnitromethane (1e) with phenylacetylene under various reaction conditions.
Entry
Catalyst (mol-%)
T [°C]
t [h]
Yield [%][a]
Ratio
16e/29[
b]
16e
29
1
2
3
4
5
6
7
8
9
none
60
60
60
60
60
40
40
60
60
60
60
60
24
4
8
24
24
24
60
4
–
0.9
2
–
–
–
–
–
–
9
25
–
16
10
14
18
22
32
NMP (20)
NMP (20)
NMP (20)
Cu(OAc)
Cu(OAc)
Cu(OAc)
Cu(OAc)
Cu(OAc)
73
75
22
78
7
78
81
86
82
8.4
3.0
–
4.8
0.7
6
4.6
4.0
2.6
2
2
2
2
2
(5), NMP (20)
(5), NMP (20)
(5), NMP (20)
(5), NMP (20)
(5), NMP (20)
8
10
11
12
Cu (5), NMP (20)
Cu(OAc) (2.5), NMP (10)
Cu (2.5), NMP (10)
24
24
24
2
[
a] Yield determined by 1H NMR spectroscopy with the use of an internal standard. [b] Molar ratio determined by analysis of the crude reaction mixture by
H NMR spectroscopy.
1
Eur. J. Org. Chem. 0000, 0–0
www.eurjoc.org
4
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
suggests that the results dramatically depend on the reaction higher if half the amount of the catalyst was used (Table 1); in
II
conditions. Thus, variations in the NMP/Cu catalytic system ap- other cases, the amount of catalyst could be reduced without
plied to the model reaction of benzoylnitromethane (1e) with worsening the results.
phenylacetylene gave the results detailed in Table 2 (the ratio
between yields of main products 16e and 29 is reported in the
Diethylnitrophosphonate
last column). The use of base alone required a reaction time of 3-Phosphorylisoxazoles prepared from nitro compound 1f are
2
4 h to obtain 16e in 73 % yield (Table 2, entries 2–4), whereas rarely reported in the literature and are prepared by using a
[
48]
the same result was observed after only 8 h upon the addition stoichiometric amount of POCl3.
The catalytic direct proce-
II
of Cu (Table 2, entry 9), even at a lower temperature in 60 h dure herein described allows analogous compound 21f to be
(
(
Table 2, entry 7). Copper powder catalyzed the reaction as well obtained in fair yield (Table 1, entry 20).
Table 2, entry 10 vs. 5). The best results were achieved upon
Nitroalkanes
using a lower amount of the catalyst (Table 2, entries 11 and
1
1
2), and the highest selectivity was observed towards isoxazole Catalytic condensations of alkyne dipolarophiles with nitro-
6e. Similarly, we previously noticed that with N-methylimidaz- alkanes such as nitroethane and nitropentane are so far un-
ole, isoxazole 16e was obtained in 97 % yield provided that the known. One attempt with the use of the PPA/SiO catalytic sys-
2
[
49]
amount of the catalyst was far below the stoichiometric tem in refluxing toluene was reported to fail. Under the usual
value;
creased,
[
30]
otherwise, the proportion of furazan 29 formed in- conditions, the [Cu]/NMP catalytic system allows fair yields of
[
47]
[31a]
as also observed by others.
The yields obtained the expected condensation products between phenylacetylene
in the latter case (68 %) are in agreement with those obtained and nitroethane (1g) or nitropentane (1h) to be obtained (33
in our laboratory. Catalysis as in entries 10 and 12 (Table 2) or 39 % respectively; Table 1, entries 21 and 22). The yields are
applied to several terminal alkynes afforded acceptable results similar to those previously reported with the use of dehydrating
in terms of the yield and furazan side-product formation (see agents.[
50–52]
Both isomers are observed in the reactions of
Table 1). Corresponding 5-substituted isoxazoles 16e–20e were nitroethane and nitropentane; for the latter, analysis of the
1
obtained regioselectively (Table 1) along with trace amounts of crude reaction mixture by H NMR spectroscopy showed the
byproducts (mainly furazans). The yields of 16e and 18e were presence of a minor amount of 3-butyl-4-phenylisoxazole
Table 3. Condensation versus oxidative coupling; dependence on reaction conditions.[a]
R1
Catalyst, R CH
1
NO
2
, time
Yield [%][b]
Entry
2
30
Isoxazole
1
2
3
4
5
6
7
8
9
–
–
–
–
–
CO
CO
Me
Me
Bu
Bu
Bu
Bu
Bu
Bu
Bu
Bu
DABCO (20), 24 h
DABCO (20), Cu (OAc)
DABCO (20), Cu (OAc)
NMP (20), Cu (OAc)
NMP (100), Cu (OAc)
DABCO (20), Cu (OAc)
NMP (20), Cu (OAc)
NMP (100), Cu (OAc)
NMP (100), Cu (OAc)
DABCO (100), Cu (OAc)
DABCO (20), Cu (OAc)
NMP (20), Cu (OAc) (5), 1h (150), 96 h
NMP (100), Cu (OAc)
NMP (100), Cu (OAc)
NMP (100), Cu (OAc)
0
–
–
–
–
2
2
(5), 24 h
(5), 24 h
(5), 24 h
(5), 24 h
(5), 1a (250), 24 h
(5), 1a (150), 24 h
(5), 1g (250), 96 h
(5), 1g (250), 96 h
26
14[
9
c]
2
2
16
7
10
14
–
2
Et
Et
2
2a, 71
2a, 47
22g, 33
22g, 11
23h, 0
23h,8
23h,12
23h,39
23h,7
23h,10
23h,31
23h,50
2
2
2
11[
70
47
62
28
c]
2
10
11
12
13
14
15
16
17
2
(5), 1h (250), 120 h
2
(5), 1h (150), 96 h
2
2
(5), 1h (250) 96 h
(5), 1h (250), 96 h
(20), 1h (250), 96 h
[
c]
2
2
23
57[
–
c]
TMEDA (50), Cu (OAc)
TMEDA (100), Cu (OAc)
2
(5), 1h (250), 96 h
(5), 1h (250), 96 h
2
6
[
[
3
a] Reaction conditions: catalyst (mol-%), 1 (mol-%), 60 °C, CHCl , in air (unless otherwise indicated). [b] Yield of isolated product after chromatography.
c] Under an argon atmosphere.
Eur. J. Org. Chem. 0000, 0–0
www.eurjoc.org
5
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
(
(
23′h) (less than 5 %) along with 3-butyl-5-phenylisoxazole to be unsuited to oxidative coupling. Indeed, the proportion of
[
39,40]
23h). Likewise for alkene dipolarophiles,
the reaction did isoxazole compared to diyne appeared to be higher in these
not occur in the absence of copper or by using DABCO as the examples (Table 3, entry 17 vs. 13).
base in a stoichiometric amount (Table 3, entry 10). Low yields
of 3-alkylisoxazoles 22g and 23h were accompanied by nearly
complete conversion of phenylacetylene. This suggested that a
Conclusions
competitive process was present, owing to the fact that the
reactivity of nitroalkanes is lower than that of activated nitro
compounds.
Alkyne dipolarophiles are known to condense with active pri-
mary nitro compounds to isoxazoles under base catalysis. This
paper revealed the advantages of a catalyst containing copper
in addition to a base. Thus, active nitro compounds reacted
faster with improved yields, and the reaction could be extended
to electron-poor alkynes. Even nitroalkanes condensed with
phenylacetylene to isoxazoles. However, the most remarkable
feature of this catalytic system was the enhanced selectivity
towards condensation to isoxazoles over various competitive
side reactions. The results indicate the general applicability of
this method for the preparation of 3,5-disubstituted isoxazoles.
Copper-Catalyzed Oxidative Coupling of Terminal Alkynes
The well-known oxidative coupling of terminal alkynes to con-
jugate diynes in the presence of Cu salts and base was first
[
53]
reported by Glaser on phenylacetylene,
and others later
[
54]
slightly modified the reaction conditions; the process is now
[
55]
known as the Glaser–Hay reaction.
A wide variety of modi-
fied coupling conditions have been described, including varia-
tions in the oxidant, ligand, solvent, as well as oxidation state
of the added copper catalyst. Among these, copper(II) acetate
with an organic base (e.g., DABCO or piperidine) in dichloro- Experimental Section
methane at room temperature with air admittance was also
General Methods: Melting points were determined in open capil-
lary tubes with a Stuart Scientific SMP3 melting-point apparatus.
Chromatographic separations were performed on silica gel 60 (40–
[
56,57]
recently reported.
These conditions are very similar to
those we employed for the condensation of nitro compounds
with alkynes; therefore, a possible competition between the 6.3 μm) with analytical-grade solvents, driven by a positive pressure
[
58]
two reactions was considered.
of air; R values refer to TLC (visualized with UV light and/or by
f
Thus, we verified that in the absence of nitro compounds, dipping the plates into a solution of anisaldehyde followed by heat-
ing with a heat gun) performed on 25 mm silica-gel plates (Merck
F254) with the eluent indicated for column chromatography. For
phenylacetylene gave diyne 30 (Table 3, entries 2–5) in various
yields depending on the catalytic system employed. Diyne 30
gradient column chromatography, the R values refer to the more
f
was not obtained in the absence of copper (Table 3, entry 1).
polar eluant. Solvents were removed by evaporation with the use
Similar results were obtained from 1-octyne (29 %; conditions
1
13
of a rotary evaporator at room temperature. H NMR and C NMR
spectra were recorded with a Varian Mercuryplus 400 spectrometer
as in Table 3, entry 3) and from 1-(pyrrolidin-1-yl)prop-2-yn-1-
one (12 %; conditions as in Table 3, entry 4). Only reactions of
phenylacetylene with nitro compounds were examined in detail
1
13
(
operating at 400 MHz for H and 100.58 MHz for C) unless other-
31
wise stated. P NMR spectra were recorded with a Bruker spectrom-
eter (operating at 162 MHz). The H NMR spectroscopic data are
1
(
Table 3, entries 6–17).
The observed yields of the two products for different reac- reported as [multiplicity, coupling constant(s) in Hz, integration];
tions and conditions, reported in Table 3, show that the con- the multiplicity is denoted by s = singlet, d = doublet, t = triplet,
q = quartet, quint. = quintet, m = multiplet or unresolved, br. =
densation of nitroalkanes to isoxazole was favored more with
broad signal. The multiplicities of the 13C NMR signals (s, d, t, q; for
NMP than with DABCO and clearly also by an excess amount of
compound 20e the multiplicity for C–H are reported along with C–
the nitroalkane (Table 3, entries 12 and 13). The presence of air
ensured that copper was maintained in the Cu oxidation state.
1
13
P coupling constants) and the H and C signals, if possible, were
assigned by means of gCOSY, gHSQC, and gHMBC experiments.
Chemical shifts were determined relative to the residual solvent
II
Thus, experiments performed under an argon atmosphere led
[
59]
II
to reduced amounts of both products, because Cu was con-
1
13
peak (CHCl : 7.24 ppm for H NMR and 77.0 ppm for C NMR). ESI
3
[
60]
sumed as a stoichiometric oxidant to 30,
condensation to the isoxazole resulted in loss of the catalyst sample solution directly into the ESI chamber by syringe pump)
Table 3, entries 9 and 14). In fact, the overall yields of the with a ThermoFisher LCQ-Fleet ion-trap instrument, and spectra
and furthermore,
(electrospray ionization) mass spectra were recorded (infusing the
(
II
+
products increased if the amount of Cu was raised to 20 mol- were recorded by using the ESI technique. EI (electron impact)
mass spectra (at ionization voltage of 70 eV) were obtained by us-
%
(Table 3, entry 15). The yields observed in chloroform for
ing a Shimadzu QP5050A quadrupole-based mass spectrometer. CI
(chemical ionization) mass spectra (MeOH) were obtained by using
a Varian Saturn 2200 mass spectrometer interfaced to a Varian CP-
the condensations of alkynes with activated nitro compounds
[
18]
catalyzed by base only
not largely differ.
or by base and copper (Table 1) did
3800 gas chromatograph. Ion mass/charge (m/z) ratios are reported
In reactions of nitroalkanes with phenylacetylene, moderate
yields of isoxazoles were obtained only in the presence of cop-
as values in atomic mass units followed by the intensities relative
to the base peak in parentheses. IR spectra were recorded with a
per (Table 1, entries 21 and 22), besides considerable amounts Perkin–Elmer 881 spectrophotometer. Elemental analyses were per-
of products resulting from oxidative coupling (Table 3, entries 8 formed with a Perkin–Elmer 240C Elemental Analyzer apparatus. All
and 13). Given that the kind of base was found to affect both compounds were named by using Autonom (Beilstein Information
Systems) and were modified as appropriate.
competitive reactions, some experiments were performed by
using N,N,N′,N′-tetramethylethylenediamine (TMEDA) as the Materials: Commercially available (Lancaster and Aldrich) ethyl
[
61]
base (Table 3, entries 16 and 17) because this was reported
nitroacetate (1a), methyl nitroacetate (1b), benzoylnitromethane
Eur. J. Org. Chem. 0000, 0–0
www.eurjoc.org
6
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
2 H, CH N), 3.59–3.66 ppm (m, 2 H, CH N). 3C NMR (50 MHz, CDCl3):
1
(1e), nitroethane (1g), nitropentane (1h), and organic bases, 99 %,
2
2
were used as supplied. Diethyl (nitromethyl)phosphonate (1f) was
prepared following a previously reported procedure.[ N-Methyl-2-
nitroacetamide (1c) was prepared following a previously reported
δ = 24.4 (t, CH ), 25.1 (t, CH ), 45.1 (t, CH N), 47.9 (t, CH N), 76.8 (s,
2 2 2 2
62]
+
CCO), 77.1 (d, CH), 151.2 ppm (s, CO). MS (ESI ): m/z (%) = 146 (100)
+
+
+
[M + Na] , 124 (25) [M + H] . MS (EI): m/z (%) = 123 (32) [M] , 122
procedure.[ CHCl (ethanol-free) was filtered through a short pad
28]
(38) [M – H] , 95 (16), 70 (54), 67 (64), 53 (100) [HCCO] . IR (KBr):
+
+
3
of potassium carbonate just before use. Copper(II) acetate and cop-
per powder were used as supplied. Experiments performed under
an atmosphere of argon were conducted with degassed CHCl3,
which was obtained by three freeze–pump–thaw cycles.
ν = 3301 (m) [≡ C–H], 2976 (m) [C–H], 2955 (m) [C–H], 2883 (m),
˜
2113 (m) [C≡ C], 1618 (s) [C=O], 1431 (s), 1340 (m), 1251 (w), 1226
–
1
(w), 1191 (w) cm . C H NO (123.15): calcd. C 68.27, H 7.37, N 11.37;
7
9
found C 68.24, H 7.57, N 10.97.
Kinetic Profile for Reactions between Ethyl Nitroacetate (1a)
and Phenylacetylene: Different catalysts or none were screened in
an apparatus in which 6–8 reactions were performed simultane-
ously. A mixture of the catalyst (DABCO 0.0424 mmol or Cu
General Procedure for the Preparation of Isoxazoles: Chloroform
(2086 mg, 1.40 mL) was added to a mixture of nitro compound
1a–h (2.5 equiv.), the catalyst (copper powder or copper acetate
0.05 equiv. and NMP or DABCO 0.2 equiv.), and the alkyne (0.404–
0.514 mmol), and then the mixture was maintained at 60 °C whilst
stirring in a sealed tube. After the indicated time, the solvent was
removed and the crude residue was purified by column chromatog-
raphy on silica gel. Significant variations in the amounts employed
0
.0212 mmol/DABCO 0.0424 mmol), phenylacetylene (0.424 mmol),
ethyl nitroacetate (1a, 1.06 mmol), and CDCl (1.4 mL) was stirred
3
at 60 °C in a sealed tube for the indicated time. After the requested
time, a portion was withdrawn, diluted with CDCl (0.6 mL), and
3
1
the H NMR spectrum was recorded. The percentage of phenylacet- and conditions are mentioned individually (Table 1).
ylene (as molar ratio) was evaluated by integrating the 4-H proton
Ethyl 5-Phenylisoxazole-3-carboxylate (2a): From 1a and phenyl-
signal of cycloadduct 2a [δ = 6.91 (s) ppm] and the acetylenic pro-
acetylene (43.3 mg) in 94 % yield (87.0 mg, yellowish powder) by
ton of phenylacetylene [δ = 3.05 (s) ppm]. Without catalyst, no con-
using DABCO (0.1 equiv.)/Cu(OAc) (0.05 equiv.) as catalyst at 60 °C
2
version was observed. All experiments were replicated at least once
with similar results (Figure 1).
for 23 h. Eluant: hexane/EtOAc = 8:1 (R = 0.26), m.p. 48–49 °C
f
[
64]
(
ref. 48–50 °C). C H NO (217.22): calcd. C 66.35, H 5.10, N 6.44;
12 11 3
Kinetic Profile for Reactions between Ethyl Nitroacetate (1a)
and 1-(Pyrrolidin-1-yl)prop-2-yn-1-one: Conversions and yields
were determined by GC and are based on the alkyne used. Gas
chromatographic analysis was conducted by using a Shimadzu GC-
found C 66.14, H 4.99, N 6.58. The spectroscopic data were identical
[
28]
to those previously reported.
The reaction conducted by using
NMP (0.2 equiv.)/Cu(OAc) (0.05 equiv.) as the catalyst gave 2a in
2
87 % yield. The latter sample exhibited spectral and analytical data
in agreement with those reported above.
2
010 on a 0.25 mm × 30 m Simplicity-5 capillary column. Typical
conditions used for the gas chromatographic analysis were: injector
T = 250 °C, constant flow 1.0 mL min , initial T = 150 °C, hold time
Ethyl 5-Hexylisoxazole-3-carboxylate (3a)
–
1
3
2
(
min, 10 °C min–1 to 230 °C then hold time 3 min, 5 °C min to
–1
With CuII Salt: From 1a and 1-octyne (45.4 mg) in 82 % yield
–
1
50 °C, then hold time 5 min, 5 °C min to 280 °C. Retention times
(77.3 mg, clear oil) by using NMP/Cu(OAc)
48 h. Eluant: hexane/EtOAc = 20:1 (R = 0.22). H NMR (CDCl
0.87 (t, J = 6.8 Hz, 3 H; CH CH ), 1.27–1.34 (m, 6 H, 3 CH ), 1.38 (t,
J = 7.2 Hz, 3 H; OCH CH ), 1.68 (quint., J = 7.6 Hz, 2 H; CH ), 2.77 (t,
J = 7.6 Hz, 2 H; C-5CH ), 4. 40 (q, J = 7.2 Hz, 2 H; OCH CH ), 6.37 ppm
.0212 mmol or none), ethyl nitroacetate (1a, 1.06 mmol), 1-(pyrrol- (s, 1 H, 4-H). 13C NMR (CDCl
): δ = 14.0 (q; CH CH ), 14.1 (q;
CH CH O), 22.4 (t; CH ), 26.7 (t; CH ), 27.3 (t; CH ), 28.6 (t; CH ), 31.3
one (internal standard, 26.1 mg), and CHCl (1.4 mL) was stirred at (t; CH ), 62.0 (t; OCH CH ), 101.4 (d; C-4), 156.3 (s; C-3 or CO), 160.3
(s; C-3 or CO), 175.7 ppm (s; C-5). MS (ESI , MeOH): m/z (%) = 226
2
as catalyst at 60 °C for
1
tR) are referred to the above conditions. Relative response factors
f
): δ =
3
were derived from a reference solution obtained by weighing sub-
strate, products, and internal standard. A mixture of the catalyst
3
2
2
2
3
2
(
0
NMP 0.0848 mmol or NMP 0.0848 mmol and Cu(OAc)2
2
2
3
3
3
2
idin-1-yl)prop-2-yn-1-one (0.424 mmol), 2,4-dimethoxyacetophen-
3
2
2
2
2
2
3
2
2
3
+
6
0 °C in a sealed tube, and the progress of the reaction was moni-
+
+
tored by GC analysis. A portion was withdrawn (0.01 mL) at regular
intervals, which was diluted with EtOAc (0.1 mL) and then analyzed
by GC. The conversion was evaluated by integrating the signals of
(10) [M + H] , 248 (100) [M + Na] . IR (CDCl
3
): ν˜ = 2958 (s) (C–H),
(s), 1248 (s), 1213 (s) cm . C12H19NO (225.28): calcd. C 63.98, H
3
2931 (s) (C–H), 2871 (m) (C–H), 1732 (s) (C=O), 1591 (m) (C=N), 1462
–
1
1
-(pyrrolidin-1-yl)prop-2-yn-1-one (tR = 5.90) and 2,4-dimethoxy-
8.50, N 6.22; found C 64.38, H 7.88, N 5.99.
acetophenone (tR = 9.80). The yield was evaluated by integrating
the signals of the internal standard (t = 9.80), isoxazole 11′a (t =
0
With Cu : From 1a and 1-octyne (45.5 mg) in 76 % yield (71.1 mg,
R
R
clear oil) by using NMP/Cu powder as catalyst at 60 °C for 24 h.
Eluant: as above. C H NO (225.28): calcd. C 63.98, H 8.50, N 6.22;
found C 63.50, H 7.64, N 6.25. The spectroscopic data were identical
to those reported above.
1
3.4), and isoxazole 11a (t = 16.3). Without catalyst, no conversion
R
12
19
3
was observed. All experiments were repeated at least once with
similar results (Figure 2).
1
-(Pyrrolidin-1-yl)prop-2-yn-1-one: Prepared from methyl prop-
Ethyl 5-Cyclopropylisoxazole-3-carboxylate (4a)
[
63]
iolate as reported in the literature with slight modification.
Methyl propiolate (0.84 mL, 10 mmol) wad added dropwise to a With Cu Salt: From 1a and cyclopropylacetylene (30.8 mg) in 90 %
II
stirred solution of pyrrolidine (0.83 mL, 10 mmol) in water (0.50 mL)
and MeOH (0.70 mL) at –50 °C. After 5 h, the mixture was warmed
yield (76.0 mg, clear oil) by using NMP/Cu(OAc) as catalyst at 60 °C
2
1
for 24 h. Eluant: hexane/EtOAc = 7:1 (R = 0.30). H NMR (CDCl ):
f
3
up to room temperature while adding 2
M
HCl (40 mL). After 16 h,
δ = 0.96–1.02 (m, 2 H, CHCH ), 1.06–1.12 (m, 2 H, CHCH ), 1.38 (t,
2
2
the mixture was extracted with CH Cl (4 × 20 mL). The combined
J = 7.2 Hz, 3 H; CH CH O), 2.02–2.10 (m, 1 H, CHCH ), 4.40 (q, J =
2
2
3
2
2
13
organic layer was washed with aqueous satd. NaHCO (20 mL), wa-
7.2 Hz, 2 H; CH CH O), 6.28 ppm (s, 1 H, 4-H). C NMR (CDCl ): δ =
3
3
2
3
ter (20 mL), and brine (20 mL); dried with Na SO ; filtered; and
8.1 (d; CHCH ), 8.8 (t, 2 C; 2 CHCH ), 14.1 (q; CH CH O), 62.0 (t;
2 2 3 2
2
4
concentrated in vacuo. The crude solid residue was washed with
CH CH O), 99.3 (d; C-4), 156.4 (s; C-3 or CO), 160.2 (s; C-3 or CO),
176.8 ppm (s; C-5). MS (ESI , MeOH): m/z (%) = 182 (100) [M + H] .
3 2
+
+
hexane (3 × 4 mL) to yield the title amide as a yellowish powder
1
(
0.558 g, 58 %), m.p. 89–91 °C (ref.[63] 90–91 °C). H NMR (200 MHz, IR (CDCl ): ν˜ = 2985 (w) [C–H], 2939 (w) [C–H], 1731 (s) [C=O], 1595
3
–1
CDCl ): δ = 1.86–1.95 (m, 4 H, 2 CH ), 3.0 (s, 1 H, CH), 3.41–3.48 (m,
(m) [C=N], 1468 (m), 1252 (s), 1228 (s), 1187 (m), 1020 (m) cm .
3
2
Eur. J. Org. Chem. 0000, 0–0
www.eurjoc.org
7 © 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
1
C H NO (181.19): calcd. C 59.66, H 6.12, N 7.73; found C 59.51, H
72 h. Eluant: hexane/EtOAc = 2:1 (R = 0.32). H NMR (CDCl ): δ =
9
11
3
f
3
5
.64, N 7.59.
1.38 (t, J = 7.2 Hz, 3 H; CH CH ), 2.08 (q, J = 7.2 Hz, 2 H; CH ), 2.42
3
2
2
0
(t, J = 6.8 Hz, 2 H; CH
2
), 2.98 (t, J = 7.6 Hz, 2 H; C-5CH
2
), 4.40 (q, J =
With Cu : From 1a and cyclopropylacetylene (28.2 mg) in 88 %
13
7
.2 Hz, 2 H; OCH ), 6.48 ppm (s, 1 H, 4-H). C NMR (CDCl ): δ = 14.1
2
3
yield (67.6 mg, clear oil) by using NMP/Cu powder as catalyst at
0 °C for 24 h. Eluant: as above. C H NO (181.19): calcd. C 59.66,
H 6.12, N 7.73; found C 59.45, H 5.88, N 7.65. The spectroscopic
data were identical to those reported above.
(
q; CH CH ), 16.5 (t; CH ), 23.2 (t; CH ), 25.4 (t; CH ), 62.2 (t; OCH ),
3 2 2 2 2 2
6
9 11 3
1
3
02.4 (d; C-4), 118.4 (s; CN), 156.5 (s; CO or C-3), 159.8 (s; CO or C-
+
), 172.5 ppm (s; C-5). MS (ESI , MeOH): m/z (%) = 231 (100) [M +
+
+
Na] 439 (30) [2M + Na] . IR (CDCl ): ν˜ = 2982 (w) (C–H), 2956 (w)
,
3
Ethyl 5-Hydroxymethylisoxazole-3-carboxylate (5a): From 1a
and propargyl alcohol (23.8 mg) in 70 % yield (51.0 mg, clear oil)
by using NMP/Cu(OAc) as catalyst at 60 °C for 24 h. Eluant: hexane/
EtOAc = 3:1 (R = 0.24). C H NO (171.15): calcd. C 49.12, H 5.30, N
.18; found C 49.11, H 5.25, N 7.97. The spectroscopic data were
identical to those previously reported.
(C–H), 2870 (w) (C–H), 2250 (m) (C≡ N), 1800 (w), 1731 (s) (C=O),
1593 (m) (C=N), 1464 (m), 1425 (m), 1296 (m), 1258 (m), 1210 (s),
–1
2
1098 (m), 1021 (m) cm . C H N O (208.21): calcd. C 57.68, H
5.81, N 13.45; found C 57.61, H 5.39, N 12.86.
10 12 2 3
f
7
9
4
8
[30]
Ethyl 5-(Diethoxymethyl)isoxazole-3-carboxylate (9a): From 1a
and 3,3-diethoxyprop-1-yne (52.4 mg) in 68 % yield (67.6 mg, clear
oil) by using NMP/Cu(OAc)2 as catalyst at 60 °C for 24 h. Eluant:
Ethyl 5-(2-Hydroxyethyl)isoxazole-3-carboxylate (6a)
With CuII Salt: From 1a and 3-butyn-1-ol (34.9 mg) in 77 % yield
70.9 mg, clear oil) by using NMP/Cu(OAc) as catalyst at 60 °C for
6 h. Eluant: hexane/EtOAc = 4:3 (R = 0.23). H NMR (CDCl ): δ =
hexane/EtOAc = 9:1 (R
7.0 Hz, 6 H; 2 CH CH O), 1.41 (t, J = 7.2 Hz, 3 H; CH
(q, J = 7.0 Hz, 4 H; 2 CH CH O), 4.44 (q, J = 7.2 Hz, 2 H; CH
5.67 (s, 1 H, CHO), 6.75 ppm (s; 4-H). C NMR (CDCl
= 0.38). 1H NMR (CDCl
3
): δ = 1.25 (t, J =
CH OCO), 3.64
CH OCO),
): δ = 14.1 (q;
O), 61.9 (t, 2 C; 2 CH CH O), 62.2
OCO), 94.9 (d; CHO), 103.6 (d; C-4), 156.2 (s; C-3 or CO),
f
(
3
2
3
2
2
1
4
1
3
6
3
2
3
2
f
3
13
.39 (t, J = 7.2 Hz, 3 H; CH CH O), 3.06 (t, J = 6.0 Hz, 2 H; CH C-5),
3
3
2
2
.97 (q, J = 5.3 Hz, 2 H; CH OH), 4.41 (q, J = 7.2 Hz, 2 H; CH CH O),
CH
(t; CH
3
CH
2
OCO), 15.0 (t, 2 C; 2 CH
3
CH
2
3
2
2
3
2
.53 ppm (s; 4-H). 1 C NMR (CDCl ): δ = 14.1 (q; CH CH O), 30.2 (t;
3
3
2
CH
3
3
2
+
CH C-5), 60.0 (t; CH OH), 62.1 (t; CH CH O), 102.7 (d; C-4), 156.6 (s;
C-3 or CO), 160.1 (s; C-3 or CO), 172.5 ppm (s; C-5). MS (ESI , MeOH):
159.8 (s; C-3 or CO), 171.2 ppm (s; C-5). MS (ESI , MeOH): m/z (%) =
2
2
3
2
+
+
243 (100) [M]
IR (CDCl
): ν˜ = 2982 (m) [C–H], 2932 (w) [C–H], 2898
.
3
+
m/z (%) = 186 (100) [M + H] . IR (CDCl ): ν = 3620 (w) [O–H], 2984 (w) [C–H], 1734 (s) [C=O], 1600 (w) [C=N], [1472 (w), 1457 (w), 1446
3
˜
–
1
(
[
w) [C–H], 2939 (w) [C–H], 2892 (w) [C–H], 1733 (s) [C=O], 1596 (m) (w), 1251(s) cm . C11H17NO (243.11): calcd. C 54.31, H 7.04, N 5.76;
5
–
1
C=N], 1462 (m), 1214 cm (s). C H NO (185.18): calcd. C 51.89, H
found C 53.98, H 6.63, N 5.34.
8
11
4
5
.99, N 7.56; found C 51.73, H 5.64, N 8.14.
3
-Ethyl Isoxazole-3,5-dicarboxylate 5-Methyl Ester (10a) and
0
With Cu : From 1a and 3-butyn-1-ol (28.8 mg) in 68 % yield
Isoxazole-3,4-dicarboxylic Acid 3-Ethyl Ester 4-Methyl Ester (10′
(51.8 mg, clear oil) by using NMP/Cu powder as catalyst at 60 °C for
a): From 1a and methyl propiolate (35.6 mg) in 40 % overall yield
4
7
8 h. Eluant: as above. C H NO (185.18): calcd. C 51.89, H 5.99, N
.56; found C 51.91, H 5.60, N 7.62. The spectroscopic data were
(34 mg, mixture of isomers, yellowish oil) by using NMP/Cu(OAc)
as catalyst at 60 °C for 60 h. Eluant: hexane/EtOAc = 4:1 (R = 0.22).
, mixture of isomers): δ = 1.33–1.46 (m, 3
H, CH CH ), 3.98 (s, 3 H, OCH ), 4.34–4.56 (m, 2 H, OCH CH ), 7.30
2
8
11
4
f
1
identical to those reported above.
H NMR (200 MHz, CDCl
3
3
2
3
2
3
Ethyl 5-(1-Hydroxycyclohexyl)isoxazole-3-carboxylate (7a)
With CuII Salt: From 1a and 1-ethynyl-cyclohexanol (53.4 mg) in
(s, 1/2 H; 4-H), 8.91 ppm (s, 1/2 H; 5-H).
Ethyl 5-(Pyrrolidine-1-carbonyl)isoxazole-3-carboxylate (11a)
and Ethyl 4-(Pyrrolidine-1-carbonyl)isoxazole-3-carboxylate
7
6 % yield (78.8 mg, clear oil) by using NMP/Cu(OAc) as catalyst at
2
1
6
0 °C for 48 h. Eluant: hexane/EtOAc = 9:3 (R = 0.30). H NMR
f
(11′a)
(CDCl ): δ = 1.38 (t, J = 7.2 Hz, 3 H; CH CH O), 1.50–1.78 (m, 6 H, 3
3
3
2
CH ), 1.81–1.90 (m, 2 H, CH ), 1.91–2.00 (m, 2 H, CH ), 2.12 (s, 1 H,
With CuII Salt: From 1a and 1-(pyrrolidin-1-yl)prop-2-yn-1-one
(52.6 mg) by using NMP/Cu(OAc)2 as catalyst at 60 °C for 24 h.
Purification (hexane/EtOAc = 1:1) gave 11a (74.0 mg, 73 %, yellow-
ish oil, R = 0.33) and diyne 32 (R = 0.38) containing trace amounts
2
2
2
13
OH), 4.41 (q, J = 7.2 Hz, 2 H; CH CH O), 6.56 ppm (s; 4-H). C NMR
3
2
(
(
(
CDCl ): δ = 14.1 (q; CH CH O), 21.5 (t, 2 C; 2 CH ), 25.0 (t; CH ), 36.5
3 3 2 2 2
t, 2 C; 2 CH ), 62.1 (t; CH CH O), 70.4 (s; COH), 100.5 (d; C-4), 156.2
2
3
2
f
f
+
s; C-3 or CO), 160.0 (s; C-3 or CO), 179.8 ppm (s; C-5). MS (ESI ,
1
of 11′a. Data for 11a: H NMR (CDCl ): δ = 1.39 (t, J = 7.2 Hz, 3 H;
3
+
MeOH): m/z (%) = 240 (100) [M + H] . IR (CDCl ): ν˜ = 3592 (w)
3
CH CH ), 1.88–2.04 (m, 4 H, 2 CH ), 3.63 (t, J = 6.6 Hz, 2 H; CH N),
3
2
2
2
[O–H], 2984 (w) [C–H], 2941 (s) [C–H], 2860 (m) [C–H], 1733 (s) [C=
3
7
.83 (t, J = 6.6 Hz, 2 H; CH N), 4.42 (q, J = 7.2 Hz, 2 H; OCH CH ),
2
2
3
O], 1601 (w) [C=N], 1458 (w), 1449 (w), 1252 (s), 1205 (s), 1020 (w)
13
.30 ppm (s, 1 H, 4-H). C NMR (CDCl ): δ = 14.1 (q; CH CH ), 23.7
3
3
2
–1
cm . C H NO (239.12): calcd. C 60.24, H 7.6, N 5.85; found C
12
17
4
(t; CH ), 26.0 (t; CH ), 47.4 (t; CH N), 47.8 (t; CH N), 62.5 (t; OCH ),
2 2 2 2 2
6
0.01, H 7.30, N 5.62.
1
08.5 (d; C-4), 154.8 (s; CON), 156.3 (s; C-3 or CO Et), 159.1 (s; C-3
2
+
0
or CO Et), 166.2 ppm (s; C-5). MS (ESI , MeOH): m/z (%) = 239 (40)
With Cu : From 1a and 1-ethynyl-cyclohexanol (52.6 mg) in 85 %
yield (86.3 mg, greenish oil) by using NMP/Cu powder as catalyst
at 60 °C for 120 h. Eluant: hexane/EtOAc = 9:2 (R = 0.19). C H NO
2
+
+
[
(
M + H] , 261 (100) [M + Na] . IR (CDCl ): ν˜ = 2982 (m) (C–H), 2956
3
–1
m), 2883 (w), 1736 (s) (C=O), 1628 (s) (C=O), 1414 (m) cm .
f
12 17
4
C H N O (238.24): calcd. C 55.46, H 5.92, N 11.76; found C 55.45,
(239.12): calcd. C 60.24, H 7.6, N 5.85; found C 60.21, H 7.20, N 6.11.
11 14 2 4
1
H 5.92, N 11.76. Data for 11′a: H NMR (CDCl , from mixture with
The spectroscopic data were identical to those reported above.
3
3
2): δ = 1.38 (t, J = 7.2 Hz, 3 H; CH CH ), 1.76–2.02 (m, 4 H, 2 CH ),
3 2 2
Ethyl 5-(3-Cyanopropyl)isoxazole-3-carboxylate (8a)
3
.29 (m, 2 H, CH N), 3.61 (m, 2 H, CH N), 4.42 (q, J = 7.2 Hz, 2 H;
2 2
II
With Cu Salt: From 1a and hex-5-ynenitrile (38.7 mg) in 94 % yield
OCH CH ), 8.59 ppm (s, 1 H, 5-H). GC–MS (CI): m/z (%) = 239 (100)
2 3
+
(
82.0 mg, clear oil) by using NMP/Cu(OAc) as catalyst at 60 °C for
[M + H] .
2
4
8 h. Eluant: hexane/EtOAc = 2:1 (R = 0.32). C H N O (208.21):
0
f
10 12 2 3
With Cu : From ethyl nitroacetate (1a) and 1-(pyrrolidin-1-yl)prop-
2
calcd. C 57.68, H 5.81, N 13.45; found C 57.57, H 5.59, N 12.61. The
spectroscopic data were identical to those reported below.
-yn-1-one (52.5 mg) by using NMP/Cu powder as catalyst at 60 °C
for 24 h. Purification as above gave 11a (68.2 mg, 67, yellowish
oil) and diyne 32 containing trace amounts of 11′a. Data for 11a:
C H N O (238.24): calcd. C 55.46, H 5.92, N 11.76; found C 55.78,
0
With Cu : From 1a and hex-5-ynenitrile (37.6 mg) in 96 % yield
(80.3 mg, clear oil) by using NMP/Cu powder as catalyst at 60 °C for
1
1 14 2 4
Eur. J. Org. Chem. 0000, 0–0
www.eurjoc.org
8
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
H 5.71, N 11.39. The spectroscopic data were identical to those
reported above.
3 CH ), 1.41 [s, 9 H, C(CH ) ], 1.67 (quint., J = 7.2 Hz, 2 H; CH ), 2.75
2
3 3
2
(t, J = 7.6 Hz, 2 H; C-5CH ), 3.27–3.38 (m, 2 H, CH N), 3.48–3.56 (m,
2
2
2
H, CH N), 4.88 (br. s, 1 H; NH), 6.38 (s; 4-H), 7.18 ppm (br. s, 1 H;
2
Methyl 5-Hexylisoxazole-3-carboxylate (12b): From 1b and 1-
octyne (46.7 mg) in 70 % yield (62.0 mg, white powder) by using
13
NH). C NMR (CDCl ): δ = 14.0 (q; CH ), 22.4 (t; CH CH ), 26.6 (t;
CH ), 27.3 (t; CH ), 28.3 (q, 3 C; 3 CH ), 28.6 (t; CH ), 31.3 (t; CH ),
3
3
2
3
2
2
3
2
2
NMP/Cu(OAc) as catalyst at 60 °C for 60 h. Eluant: hexane/EtOAc =
2
4
4
0.0 (t; CH NHCO), 40.2 (t; CH NHCO ), 79.7 [s; C(CH ) ], 100.4 (d; C-
), 156.1 (s; CO ), 158.3 (s; CO or C-3), 159.9 (s; CO or C-3), 175.5 ppm
1
2 2 2 3 3
1
6
7
6
0:1 (R = 0.26). M. p. 32–33 °C. H NMR (CDCl ): δ = 0.86 (t, J =
f
3
2
+
.8 Hz, 3 H; CH CH ), 1.24–1.38 (m, 6 H, 3 CH ), 1.69 (quint., J =
3
2
2
+
(s; C-5). MS (ESI , MeOH): m/z (%) = 362 (100) [M + Na] . IR (CDCl ):
3
.6 Hz, 2 H; CH ), 2.77 (t, J = 7.6 Hz, 2 H; C-5CH ), 3.94 (s, 3 H, OCH ),
2
2
3
ν = 3457 (w) [N–H], 3418 (w) [N–H], 2932 (m), 2857 (m), 1708 (s)
1
3
˜
.38 ppm (s, 1 H, 4-H). C NMR (CDCl ): δ = 14.0 (q, CH CH ), 22.4
3
3
2
[
C=O], 1690 (s), [C=O], 1590 (w) [C=N], 1544 (m), 1506 (s), 1457 (m),
(
t, CH ), 26.7 (t, CH C-5), 27.3 (t, CH ), 28.6 (t, CH C-5), 31.3 (t, CH ),
2 2 2 2 2
–1
1367 (m), 1252 (m), 1165 (m) cm . C H N O (339.43): calcd. C
17 29 3 4
5
2.7 (q, OCH ), 101.4 (d, C-4), 156.0 (s, CO), 160.7 (s, C-3), 175.8 (s,
3
60.15, H 8.61, N 12.38; found C 60.22, H 8.37, N 12.59.
+
+
C-5) ppm. MS (ESI , MeOH): m/z (%) = 212 (8) [M + H] , 234 (100)
+
+
[
M + Na] , 445 (12) [2M + Na] . IR (CDCl ): ν˜ = 2957 (s) [C–H], 2932
3
3-Benzoyl-5-phenylisoxazole (16e)
(s) [C–H], 2860 (m) [C–H], 1736 (s) [C=O], 1592 (m) [C=N], 1471 (m),
–
1
With Typical Amount of Catalyst: From 1e and phenylacetylene
1
249 (m), 1221 (s), 1004 (m) cm . C H NO (211.26): calcd. C
11 17 3
(41.7 mg) in 73 % yield (74.0 mg, white powder) by using NMP/
6
2.54, H 8.11, N 6.63; found C 62.59, H 8.03, N 6.76.
Cu(OAc) as catalyst at 60 °C for 18 h. The residue was dissolved in
CH Cl (10 mL), silica gel (200 mg) was added to the mixture, and
2
N-Methyl-5-phenylisoxazole-3-carboxamide (13c)
2
2
the solvent was evaporated. The silica gel with the adsorbed prod-
uct was loaded onto the top of a column of silica gel and purified
With Typical Amount of Catalyst: From 1c (2.5 equiv.) and phenyl-
acetylene (44.6 mg) in 57 % yield (53.3 mg, white powder) by using
by chromatography. Eluant: hexane/Et O = 1:13 (R = 0.24), m.p. 84–
NMP/Cu(OAc) as catalyst at 60 °C for 24 h. Eluant: hexane/EtOAc =
2
f
2
[
47]
[
30]
85 °C (ref.
84–85 °C). C H NO (249.26): calcd. C 77.10, H 4.45,
2
(
2
1
:1 (R = 0.29), m.p. 192–193 °C (ref. 192–193 °C). GC–MS (CI): m/z
16 11 2
f
+
N 5.62; found C 77.40, H 4.74, N 6.02.
%) = 203 (100) [M + H] . IR (KBr): ν˜ = 3331 (s) [N–H], 3118 (m),
981 (w) [C–H], 2945 (w) [C–H], 1669 (s) [C=O], 1566 (s), 1449 (s),
With Lower Amount of Catalyst: From 1e and phenylacetylene
–1
275 (m), 1269 (m) cm . C H N O (202.21): calcd. C 65.34, H 4.98,
1
1 10 2 2
(44.4 mg) in 80 % yield (87.0 mg, white powder) by using NMP
N 13.85; found C 65.22, H 4.84, N 14.28. The NMR spectroscopic
(
0.1 equiv.)/Cu(OAc)2 (0.025 equiv.) as catalyst at 60 °C for 24 h
data were identical to those previously reported.[
47]
[
47]
then purified as above, m.p. 84–85 °C (ref.
84–85 °C). C H NO
16 11 2
With Lower Amount of Catalyst: From 1c (2.5 equiv.) and phenyl-
acetylene (43.2 mg) in 67 % yield (56.3 mg, white powder) by using
(249.26): calcd. C 77.10, H 4.45, N 5.62; found C 76.78, H 4.26, N 5.54.
The spectroscopic data of both samples were identical to those
previously reported.
[
47]
NMP (0.1 equiv./Cu(OAc) as catalyst at 60 °C for 24 h then purified
2
as above, m.p. 192–193 °C. C H N O (202.21): calcd. C 65.34, H
1
1 10 2 2
3
-Benzoyl-5-hexylisoxazole (17e): From 1e and 1-octyne
4
.98, N 13.85; found C 65.43, H 4.89, N 14.32. The NMR spectro-
[47]
(46.6 mg) in 73 % yield (79 mg, clear oil) by using NMP/Cu(OAc) as
2
scopic data were identical to those previously reported.
catalyst at 60 °C for 24 h. Eluant: hexane/EtOAc = 20:1 (R = 0.60).
f
5
1
-Phenyl-3-N-Boc-aminoethyl Carbamate Isoxazole (14d): From
d (2.0 equiv.) and phenylacetylene (44.0 mg) in 71 % yield
1
H NMR (CDCl ): δ = 0.88 (t, J = 7.4 Hz, 3 H; CH ), 1.21–1.45 (m, 6
3
3
H, 3 CH ), 1. 73 (quint., J = 7.2 Hz, 2 H; CH ), 2.81 (t, J = 7.6 Hz, 2 H;
CH C-5), 6.50 (s, 4-H), 7.44–7.52 (m, 1 H, Ph-H ), 7.56–7.64 (m, 2
H, Ph-Hmeta), 8.24–8.30 ppm (m, 2 H, COPh-Hortho). C NMR (CDCl3):
δ = 14.0 (q; CH ), 22.4 (t; CH CH ), 26.6 (t; CH ), 27.4 (t; CH ), 28.7
(t; CH ), 31.3 (t; CH ), 101.5 (d; C-4), 128.5 (d; 2 C, Ph-Cmeta), 130.6
2
2
(
101 mg, white powder) by using NMP/Cu(OAc) as catalyst at 60 °C
2
2 para
for 19 h. Eluant: hexane/EtOAc = 2:1 (R = 0.20), m.p. 161–165 °C.
13
f
1
H NMR (CDCl ): δ = 1.41 (s, 9 H, 3 CH ), 3.26–3.45 (m, 2 H, CH N),
3
3
2
3
2
3
2
2
3
.48–3.63 (m, 2 H, CH N), 4.95 (br. s, 1 H; NHCO), 6.94 (s; 4-H), 7.34
2
2 2
(
br. s, 1 H; NHCO ), 7.40–7.52 (m, 3 H, Ph-H), 7.72–7.81 ppm (m, 2
2
(d; 2 C, Ph-Cortho), 133.8 (d, Ph-Cpara), 135.7 (s; Ph-Cipso), 161.8 (s; C-
3), 174.7 (s; C-5), 186.1 ppm (s; COPh). MS (ESI , MeOH): m/z (%) =
13
H, Ph-H). C NMR (CDCl ): δ = 28.3 (q, 3 C; 3 CH ), 40.2 (br. t, 2 C;
+
3
3
2
CH NH), 79.8 [s; C(CH ) ], 99.0 (d; C-4), 125.9 (d, 2 C; Ph-C), 126.8
+
2
3 3
280 (100) [M + Na] . IR (CDCl ): ν˜ = 3064 (w) [=C–H], 2956 (s) [C–
3
(
(
s; Ph-Cipso), 129.1 (d, 2 C; Ph-C), 130.7 (d; Ph-C), 156.4 (s; CO ), 159.0
2
H], 2932 (s) [C–H], 2860 (m) [C–H], 1662 (s) [C=O], 1599 (m), 1579
+
s; CO or C-3), 159.5 (s; CO or C-3), 171.6 ppm (s; C-5). MS (ESI ,
–1
(m), 1455 (s), 1281 (w), 1251 (m), 1217 (m), 1182 (w) cm .
+
+
MeOH): m/z (%) = 354 (100) [M + Na] , 685 (64) [2M + Na] . IR (KBr):
ν˜ = 3381 (w) [N–H], 3342 (w) [N–H], 3153 (w), 2981 (m), 2945 (w),
C H NO (257.33): calcd. C 74.68, H 7.44, N 5.44; found C 74.31, H
16
19
2
7.39, N 5.00.
1
686 (s) [C=O], 1666 (s), 1609 (w), 1548 (s), 1525 (s), 1446 (m), 1368
–
1
3-Benzoyl-5-(3-cyanopropyl)isoxazole (18e)
(m), 1275 (m), 1262 (m), 1236 (m), 1175 (m) cm . C H N O
17 21 3 4
(
1
331.37): calcd. C 61.62, H 6.39, N 12.68; found C 61.78, H 6.34, N
2.65.
With Typical Amount of Catalyst: From 1e and hex-5-ynenitrile
(40.0 mg) in 56 % yield (58.0 mg, clear oil) by using NMP/Cu(OAc)2
5
-Hexyl-3-N-Boc-aminoethyl Carbamate Isoxazole (15d)
as catalyst at 60 °C for 24 h. Eluant: hexane/EtOAc = 1:4 (R = 0.15).
f
After chromatography, isolated 18e was further washed with hex-
II
With Cu Salt: From 1d (2.0 equiv.) and 1-octyne (49.0 mg) in 58 %
yield (88 mg, white powder) by using NMP/Cu(OAc) as catalyst at
1
ane. H NMR (CDCl ): δ = 2.06–2.16 (m, 2 H, CH ), 2.46 (t, J = 7.2 Hz,
3
2
2
2
H; CH C-5), 3.03 (t, J = 7.2 Hz, 2 H; CH CN), 6.59 (s; 4-H), 7.50 (t,
2
2
6
0 °C for 19 h. Eluant: hexane/EtOAc = 2:1 (R = 0.29), m.p. 91–92 °C.
f
J = 7.6 Hz, 2 H; Ph-Hmeta), 7.63 (t, J = 7.6 Hz, 1 H; Ph-Hpara), 8.24–
C H N O (339.43): calcd. C 60.15, H 8.61, N 12.38; found C 60.12,
H 8.33, N 12.52. The spectroscopic data were identical to those
reported below.
17
29
3
4
13
8
.30 ppm (m, 2 H, COPh-Hortho). C NMR (CDCl ): δ = 16.2 (t; CH ),
3 2
2
3.3 (t; CH ), 25.4 (t; CH ), 102.7 (d; C-4), 118.4 (s; CN), 128.6 (d, 2 C;
2
2
Ph-Cmeta), 130.6 (d, 2 C; Ph-Cortho), 134.0 (d; Ph-Cpara), 135.6 (s; Ph-
0
+
With Cu : From 1d (2.0 equiv.) and 1-octyne (47.5 mg) in 43 % yield
(
for 24 h. Eluant: hexane/EtOAc = 2:1 (R = 0.29), m.p. 89–91 °C. H
Cipso), 162.0 (s; C-3), 171.6 (s; C-5), 185.6 ppm (s; COPh). MS (ESI ,
+
62 mg, white powder) by using NMP/Cu powder as catalyst at 60 °C MeOH): m/z (%) = 263 (100) [M + Na] . IR (CDCl ): ν˜ = 3142 (w) [=
3
1
C–H], 3072 (w) [=C–H], 2956 (w) [C–H], 2250 (m) [C≡ N], 1662 (s) [C=
f
NMR (CDCl ): δ = 0. 86 (t, J = 6.8 Hz, 3 H; CH ), 1.17–1.34 (m, 6 H, O], 1599 (s), 1579 (W), 1456 (s), 1428 (W), 1257 (m), 1218 (m)
3
3
Eur. J. Org. Chem. 0000, 0–0
www.eurjoc.org
9
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
–
1
[65]
1
182(m) cm . C H N O (240.26): calcd. C 69.99, H 5.03, N 11.66;
see below for spectroscopic data), m.p. 64–65 °C (ref.
66–67 °C).
14 12 2 2
1
found C 69.72, H 4.99, N 11.44.
H NMR (CDCl ): δ = 2.33 (s, 3 H, CH ), 6.34 (s; 4-H), 7.37–7.48 (m, 3
3
3
13
H, Ph-H), 7.69–7.75 ppm (m, 2 H, Ph-H). C NMR (CDCl ): δ = 11.5
3
With Lower Amount of Catalyst: From 1d and hex-5-ynenitrile
40.3 mg) in 85 % yield (88.1 mg, clear oil) by using NMP
0.1 equiv.)/Cu(OAc) (0.025 equiv.) as catalyst at 60 °C for 24 h then
purified as above. C H N O (240.26): calcd. C 69.99, H 5.03, N
1.66; found C 69.70, H 4.84, N 11.91. The spectroscopic data of
both samples were identical to those previously reported.
(
(
(
[
(
(
q; CH ), 100.1 (d; C-4), 125.7 (d, 2 C; Ph-C), 127.7 (s; Ph-Cipso), 128.8
d, 2 C; Ph-C), 129.9 (d; Ph-C), 160.3 (s; C-3), 169.7 ppm (s; C-5). MS
3
(
(
2
+
+
ESI , MeOH): m/z (%) = 160 (100) [M + H] . IR (CDCl ): ν = 3072 (w)
3
˜
14 12 2 2
=C–H], 2933 (w) [C–H], 2860 (w) [C–H], 1618 (m), 1594 (m), 1576
1
–
1
m), 1471 (m), 1455 (s), 1413 (s), 1373 (w), 1260 (w) cm . C H NO
1
0 9
159.18): calcd. C 75.45, H 5.70, N 8.80; found C 75.43, H 5.72, N
3
-Benzoyl-5-cyclopropylisoxazole (19e): From 1e and cyclo-
8.96.
propylacetylene (30.0 mg) in 70 % yield (67.0 mg, clear oil) by using
3
-Butyl-5-phenylisoxazole (23h): From 1h and phenylacetylene
NMP/Cu(OAc) as catalyst at 60 °C for 24 h. Eluant: hexane/ EtOAc =
2
(43.8 mg) in 39 % yield (33.6 mg, melting solid) by using NMP
1
2
1
7
0:1 (R = 0.21). H NMR (CDCl ): δ = 0.99–1.05 (m, 2 H, CH ), 1.09–
f
3
2
(1.0 equiv.)/copper powder (0.05 equiv.) as catalyst at 60 °C for 96 h.
.16 (m, 2 H, CH ), 2.05–2.16 (m, 1 H, CHCH ), 6.40 (s; 4-H), 7.44–
2
2
Eluant: hexane/EtOAc = 35:1 (R = 0.30). The isolated product con-
f
.52 (m, 2 H, Ph-Hmeta), 7.56–7.64 (m, 1 H, Ph-Hpara), 8.24–8.30 ppm
tained a trace amount of isoxazole 23′h [less than 5 %, detected by
1
3
(
m, 2 H, COPh-Hortho). C NMR (CDCl ): δ = 8.04 (d; CH), 8.78 (t, 2
3
1
H NMR spectroscopy: δ = 8.37 ppm (5-H)]. 1,4-Diphenylbuta-1,3-
C; CH ), 99.4 (d, C-4), 128.5 (d, 2 C; Ph-Cmeta), 130.6 (d, 2 C; Ph-Cortho),
2
diyne (30) was also isolated (12.2 mg, 28 %, R = 0.70, see below
for spectroscopic data), m.p. 27–28 °C. (ref.
f
1
1
33.9 (d; Ph-Cpara), 135.7 (s; Ph-Cipso), 161.9 (s; C-3), 175.9 (s; C-5),
[66]
1
27–28 °C). H NMR
+
86.1 ppm (s; COPh). MS (ESI , MeOH): m/z (%) = 236 (100) [M +
(200 MHz, CDCl ): δ = 0.94 (t, J = 7.4 Hz, 3 H; CH ), 1.26–1.51 (m, 2
+
3
3
Na] . IR (CDCl ): ν˜ = 3143 (w) [=C–H], 3098 (w) [=C–H], 3072 (w) [=
3
H, CH ), 1.54–1.78 (m, 2 H, CH ), 2.70 (t, J = 8.0 Hz, 2 H; CH C-3),
2
2
2
C–H], 3018 (w) [=C–H], 2956 (w) [C–H], 1662 (s) [C=O], 1594 (s) 1578
6.36 (s; 4-H), 7.27–7.49 (m, 3 H, Ph-H), 7.59–7.80 ppm (m, 2 H, Ph-
(
1
m), 1456 (s), 1433 (m), 1334 (m), 1282 (m), 1256 (s), 1227 (m)
13
H). C NMR (50 MHz, CDCl ): δ = 13.9 (q; CH ), 22.3 (t; CH ), 25.8 (t;
CH ), 30.5 (t; CH ), 99.1 (d; C-4), 125.8 (d, 2 C; Ph-Cmeta), 128.2 (s; Ph-
Cipso), 128.9 (d, 2 C; Ph-C
169.5 ppm (s; C-5). MS (ESI , MeOH): m/z (%) = 202 (100) [M + H] .
–1
3
3
2
181(m) cm . C H NO (213.23): calcd. C 73.23, H 5.20, N 6.57;
13 11 2
2
2
found C 73.21, H 4.95, N 6.58.
), 129.9 (d; Ph-Cpara), 164.7 (s; C-3),
ortho
+
+
3
-Benzoyl-5-hydroxyethylisoxazole (20e): From 1e and 3-butyn-
1
-ol (30.2 mg) in 58 % yield (54.0 mg, clear oil) by using NMP
IR (CDCl
3
): ν˜ = 3068 (w) [=C–H], 2960 (w) [C–H], 2933 (w) [C–H],
(0.1 equiv.)/Cu(OAc)2 (0.025 equiv.) as catalyst at 60 °C for 24 h.
2874 (w) [C–H], 2864 (w)[C–H], 1616 (m), 1593 (m), 1576 (m), 1466
(m), 1451 (s), 1420 (m), 913 (w), 844 (w), 748 (w) cm . C13
1
–1
Eluant: hexane/ EtOAc = 2:1 (R = 0.19). H NMR (CDCl ): δ = 3.10
H15NO
f
3
(
t, J = 6.0 Hz, 2 H; CH C-5), 3.97–4.10 (m, 2 H, CH OH), 6.64 (s; 4-H), (201.26): calcd. C 77.58, H 7.51, N 6.96; found C 77.24, H 7.20, N 6.95.
2
2
7
8
.50 (t, J = 7.6 Hz, 2 H; Ph-Hmeta), 7.62 (m, J = 7.6 Hz, 1 H; Ph-Hpara),
The reaction repeated with the use of TMEDA (1 equiv.) instead of
NMP gave 23h in 50 % yield and 30 in 6 % yield (Table 3).
1
3
.24–8.30 ppm (m, 2 H, Ph-Hortho). C NMR (CDCl ): δ = 30.2 (t;
3
CH C-5), 60.0 (t; CH OH), 102.9 (d; C-4), 128.5 (d, 2 C; Ph-Cmeta), 130.6
2
2
3
1
-Aminoethyl-5-phenylisoxazole Hydrochloride (24): Boc-amine
4d (20.1 mg, 0.0607 mmol) was dissolved in MeOH (0.5 mL), and
(
3
2
d, 2 C; Ph-Cortho), 134.0 (d; Ph-Cpara), 135.8 (s; Ph-Cipso), 162.0 (s; C-
+
), 171.6 (s; C-5), 185.9 ppm (s; COPh). MS (ESI , MeOH): m/z (%) =
the solution was cooled with ice. 6
M HCl (1 mL) was added drop-
+
40 (100) [M + Na] . IR (CDCl ): ν˜ = 3621 (w) [O–H), 3142 (w) [=C–
3
wise. After stirring for 16 h at room temperature, the mixture was
concentrated and the solid residue was triturated with diethyl ether
and carefully dried under high vacuum to give product 24 as a
H], 3072 (w) [=C–H], 2965 (w) [C–H], 2891 (m) [C–H], 1663 (s) [C=O],
1
1
599 (s), 1579 (w), 1455 (s), 1428 (w), 1263 (m), 1219 (m) 1182 (m),
–1
046 (m) cm . C H NO (217.22): calcd. C 66.35, H 5.10, N 6.45;
12
11
3
1
white powder (16.0 mg, 98 %), m.p. 245–250 °C (dec.). H NMR
found C 66.76, H 4.80, N 6.90.
(CD OD): δ = 3.22 (t, J = 6.2 Hz, 2 H; CH NCO), 3.73 (t, J = 6.2 Hz, 2
3
2
+
Diethyl (5-Hexylisoxazol-3-yl)phosphonate (21f): From 1f
H; CH
2
NH
3
), 7.16 (s; 4-H), 7.52–7.60 (m, 3 H, Ph-H), 7.89–7.94 ppm
13
+
(2.0 equiv.) and 1-octyne (48 mg) in 49 % yield (62 mg, yellowish
(m, 2 H, Ph-H). C NMR (CD
OD): δ = 38.2 (t; CH NH ), 40.9 (t;
3 2 3
oil) by using NMP/Cu(OAc)2 as catalyst at 60 °C for 72 h. Eluant:
CH NHCO), 100.0 (d; C-4), 126.9 (d, 2 C; Ph-C), 128.1 (s; Ph-Cipso),
2
1
hexane/EtOAc = 2:1 (R = 0.27). H NMR (CDCl ): δ = 0.85–0.93 (m,
130.4 (d, 2 C; Ph-C), 132.0 (d; Ph-C), 160.3 (s; CO or C-3), 162.4 (s;
f
3
+
3
H, CH ), 1.22–1.40 (m, 6 H, 3 CH ), 1.35 (t, J = 7.2 Hz, 6 H; 2
CO or C-3), 173.0 ppm (s; C-5). MS (ESI , MeOH): m/z (%) = 232 (100)
3
2
+
+
+
OCH CH ), 1.62–1.74 (m, 2 H, CH ), 2.78 (t, J = 7.6 Hz, 2 H; CH C-5),
[M + H] , 254 (16) [M + Na] , 463 (20) [2M + H] , 485 (32) [2M +
2
3
2
2
13
+
4
(
.16–4.28 (m, 4 H, 2 OCH CH ), 6.27 ppm (s, 1 H, 4-H). C NMR
CDCl ): δ = 14.0 (q; CH ), 16.2 (t, J = 6.4 Hz, 2 C; OCH CH ), 22.4
Na] . IR (KBr): ν˜ = 3550–2500 (br.), 3319 (m), 3090 (m)], 1678 (s)
2
3
3
[C=O], 1591 (m), 1562 (s), 1494 (s), 1454 (s), 1263 (m), 1170 (m).
3
3
2
3
(
6
1
t; CH ), 26.5 (t; CH ), 27.4 (d; CH ), 28.7 (t; CH C-5), 31.3 (t; CH ),
C
12
H
13
N
3
O
2
·HCl (267.72): calcd. C 53.84, H 5.27, N 15.70; found C
2
2
2
2
2
2
2
3.5 (t, JC,P = 5.8 Hz, 2 C; OCH ), 103.2 (d, JC,P = 21.2 Hz; C-4), 53.74, H 5.02, N 15.45.
2
1
3
31
56.5 (s, J = 212 Hz; C-3), 174.6 ppm (s, J = 10.5 Hz; C-5).
P
C,P
C,P
N-(2-Aminoethyl)-5-hexylisoxazole-3-carboxamide Hydrochlor-
ide (25): The same procedure as that reported for 24 was applied
to Boc-amine 15d (20.0 mg) to afford product 25 (16 mg, 98 %) as
+
NMR (CDCl ): δ = 5.19 ppm. MS (ESI , MeOH): m/z (%) = 601 (100)
[
1
C H NO P (289.31): calcd. C 53.97, H 8.36, N 4.84; found C 54.16,
H 8.42, N 4.72.
3
+
+
2M + Na] , 312 (20) [M + Na] . IR (CDCl ): ν˜ = 2931 (m), 2861 (w),
3
–
1
581 (w), 1426 (m), 1394 (w), 1256 (s) [P=O], 1026 (s) cm .
1
a white powder, m.p. 154–167 °C (dec.). H NMR (CD OD/CDCl =
3
3
13
24
4
3:1): δ = 0. 88 (t, J = 6.8 Hz, 3 H; CH ), 1.27–1.42 (m, 6 H, 3 CH ),
3
2
1.65–1.75 (m, 2 H, CH ), 2.80 (t, J = 7.6 Hz, 2 H; C-5CH ), 3.13 (t, J =
2
2
+
3
(
-Methyl-5-phenylisoxazole (22g): From 1g and phenylacetylene
43.8 mg) in 33 % yield (22.4 mg, white powder) by using NMP
5.8 Hz, 2 H; CH NHCO), 3.64 (t, J = 5.8 Hz, 2 H; CH NH ), 6.45 ppm
2
2
3
(s; 4-H). 13C NMR (CD OD/CDCl3 = 3:1): δ = 14.3 (q; CH ), 23.2 (t;
3
3
(
1.0 equiv.)/Cu(OAc) (0.05 equiv.) as catalyst at 60 °C for 96 h. Elu-
CH CH ), 27.2 (t; CH ), 28.1 (t; CH ), 29.3 (t; CH ), 32.1 (t; CH ), 37.8
2 3 2 2 2 2
2
+
ant: hexane/EtOAc = 40:1 (R = 0.15). The isolated product contained
(t; CH NH3 ), 40.3 (t; CH NHCO), 100.9 (d; C-4), 158.9 (s; CO or C-3),
f
2 2
+
a trace amount of isoxazole 22′h [less than 5 %, detected by
162.2 (s; C-3 or CO), 176.7 ppm (s; C-5). MS (ESI , MeOH): m/z (%) =
1
+
+
H NMR spectroscopy: δ= 2.40 (s, CH ), 8.42 ppm (s, 5-H)]. 1,4-Di-
240 (100) [M + H] , 252 (22) [M + Na] . IR (KBr): ν˜ = 3283 (m), 2955
3
phenylbuta-1,3-diyne (30) was also isolated (6 mg, 14 %, R = 0.70,
(m) [C–H], 2926 (m) [C–H], 2858 (m) [C–H], 1666 (s) [C=O], 1599
f
Eur. J. Org. Chem. 0000, 0–0
www.eurjoc.org
10
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
(
w) [C=N], 1550 (s), 1520 (m), 1450 (m), 1254 (w), 1169 cm–1 (m). maintained at 60 °C whilst stirring in a sealed tube. After 120 h, the
C H ClN O (275.77): calcd. C 52.26, H 8.04, N 15.24; found C solvent was removed and the crude residue was purified by column
12
22
3 2
5
2.55, H 8.27, N 15.44.
chromatography on silica gel (hexane/EtOAc = 35:1) to afford 1,4-
diphenylbuta-1,3-diyne (30) (31 mg, 70 %, R = 0.70) (Table 3, en-
try 10), m.p. 85–86 °C [ref. 82–84 °C (hexane)]. H NMR(200 MHz,
f
General Procedure for the Reaction of Benzoylnitromethane
with Phenylacetylene: Chloroform (2086 mg, 1.40 mL) was added
to the catalyst, benzoylnitromethane (1.05 mmol), and the alkyne
[
68]
1
CDCl ): δ = 7.26 7.40 (m, 6 H, Ph-H), 7.44–7.58 ppm (m, 4 H, Ph-
3
13
Hortho). C NMR (50 MHz, CDCl ): δ = 74.0 (s, 2 C; 2 C≡ C-C H ), 81.6
3
6 5
(0.424 mmol), and then the mixture was maintained at the indicated
(
s, 2 C; 2 C≡ C-C H ), 121.9 (s, 2 C; 2 Ph-Cipso), 128.4, (d, 4 C; 2
6 5
temperature whilst stirring in a sealed tube. After the indicated
time, the mixture was washed with water (2 2 mL), dried with
Na SO , and then an internal standard (3,4-dimethoxyaceto-
Ph-Cmeta), 129.2 (d, 2 C; 2 Ph-Cpara), 132.5 ppm (d, 4 C; 2 Ph-Cortho).
+
GC–MS (CI): m/z (%) = 203 (100) [M + 1] .
2
4
phenone, 24–26 mg) was added. The mixture was concentrated un- Supporting Information (see footnote on the first page of this
1
13
der reduced pressure, and a portion was dissolved in CDCl and the
H NMR spectrum was registered. Integrating the signal for COCH3
article): H NMR and C NMR spectra for 1-(pyrrolidin-1-yl)prop-2-
yn-1-one and compounds 2a–11a, 12b, 13c, 14d, 15d, 16e–20e,
21f, 22g, 23h, 24, 25, and 30–32.
3
1
[δ = 2.56 ppm (s)] of the internal standard, the signal for 4-H [δ =
7
.04 ppm (s)] of isoxazole 16e, and the signal for CH COPh [δ =
2
4
.84 ppm (s)] of furazan 29 gave the spectroscopic yields (Table 2).
Acknowledgments
Behavior of Methyl Propiolate in the Presence of NMP: Deuterio-
chloroform (1.4 mL) was added to methyl propiolate (35.6 mg, Tatiana Del Perugia, Laura Del Bimbo, Alexandra Antal, and Ve-
0
.424 mmol) and NMP (8.4 mg, 0.084 mmol), and then the dark ronica Olaru (undergraduate students of Università di Firenze)
mixture was maintained at room temperature whilst stirring in a
sealed tube controlling the progress of reaction by NMR spectro-
scopy. After 5 min, the H NMR spectrum showed the complete
conversion of methyl propiolate into dimethyl (E)-hex-2-en-4-yne-
dioate. H NMR (200 MHz, CDCl ): δ = 3.77 (s, 3 H, OCH ), 3.81 (s, 3
are acknowledged for contributions to the experimental work
during their internships. The authors thank the Italian Ministero
dell'Università e della Ricerca (MIUR) (project: COFIN-PRIN 2010-
1
2
011 prot. 20109Z2XRJ). A.B. thanks the Ente Cassa di Risparmio
1
3
3
di Firenze for a research fellowship. Maurizio Passaponti (Univer-
sità di Firenze) is acknowledged for technical support.
H, OCH ), 6.45 and 7.77 ppm (ABq, J = 16 Hz, 2 H; CH=CH and CH=
CH). GC–MS (EI): m/z (%) = 168 (16) [M] , 137 (99) [M – OMe] , 109
3
+
+
+
+ 1
(20) [M – CO Me] , 77 (100) [C H ] . H NMR spectrum was identical
2 6 5
[67]
to that previously reported.
Keywords: Homogeneous catalysis · Copper · Alkynes ·
General Procedure to Determine the Behavior of Alkynes in the Nitro compounds · Nitrogen heterocycles
Presence of [Cu]/Base System: Chloroform (2086 mg, 1.40 mL) was
added to the catalyst, the nitro compound (if used), and the alkyne
(0.418–0.424 mmol), and then the mixture was maintained at 60 °C
[1] a) A. V. Galenko, A. F. Khlebnikov, M. S. Novikov, V. V. Pakalnis, N. V.
Rostovskii, Usp. Khim. 2015, 84, 335–377 [Russ. Chem. Rev. 2015, 84, 335–
whilst stirring in a sealed tube. After the indicated time, the solvent
was removed and the crude residue was purified by column chro-
matography on silica gel (with the indicated eluant). Experiments
under an atmosphere of argon (Table 3, entries 3, 9, 14, 15) were
conducted with degassed chloroform.
3
77]; b) A. I. Kotyatkina, V. N. Zhabinsky, V. A. Khripach, Usp. Khim. 2001,
7
0, 730–743 [Russ. Chem. Rev. 2001, 70, 641–653]; c) K. B. G. Torssell,
Nitrile Oxides, Nitrones, and Nitronates in Organic Synthesis: Novel Strate-
gies in Synthesis, VCH, Weinheim, Germany, 1988, p. 138, 173; d) P. G.
Baraldi, A. Barco, S. Benetti, G. P. Pollini, D. Simoni, Synthesis 1987, 857–
8
69.
1
,4-Diphenylbuta-1,3-diyne (30): From phenylacetylene (43.7 mg)
[
2] For selected recent examples, seea) R. C. F. Jones, A. Chatterley, R. Marty,
W. M. Owton, M. R. J. Elsegood, Chem. Commun. 2015, 51, 1112–1115;
b) A.-H. Zhou, Q. He, C. Shu, Y.-F. Yu, S. Liu, T. Zhao, W. Zhang, X. Lu, L.-
W. Ye, Chem. Sci. 2015, 6, 1265–1271; c) E. E. Galenko, A. V. Galenko, A. F.
Khlebnikov, M. S. Novikov, RSC Adv. 2015, 5, 18172–18176.
3] a) J. R. Lewis, Nat. Prod. Rep. 1990, 7, 365–375; b) L. Rahbœk, C. Christo-
phersen, The Alkaloids: Chemistry and Biology (Ed.: G. A. Cordell), Aca-
demic Press, San Diego, CA, 2001, vol. 57, p. 185–233.
4] For 3,5-dimethylisoxazoles, see: a) D. S. Hewings, M. Wang, M. Philpott,
O. Fedorov, S. Uttarkar, P. Filippakopoulos, S. Picaud, C. Vuppusetty, B.
Marsden, S. Knapp, S. J. Conway, T. D. Heightman, J. Med. Chem. 2011,
54, 6761–6770; b) P. Bamborough, H. Diallo, J. D. Goodacre, L. Gordon,
A. Lewis, J. T. Seal, D. M. Wilson, M. D. Woodrow, C.-w. Chung, J. Med.
Chem. 2012, 55, 587–596; c) D. S. Hewings, O. Fedorov, P. Filippakopou-
los, S. Martin, S. Picaud, A. Tumber, C. Wells, M. M. Olcina, K. Freeman, A.
Gill, A. J. Ritchie, D. W. Sheppard, A. J. Russell, E. M. Hammond, S. Knapp,
P. E. Brennan, S. J. Conway, J. Med. Chem. 2013, 56, 3217–3227; d) D. A.
Hay, O. Fedorov, S. Martin, D. C. Singleton, C. Tallant, C. Wells, S. Picaud,
M. Philpott, O. P. Monteiro, C. M. Rogers, S. J. Conway, T. P. C. Tumber, A.
Rooney, C. Yapp, P. Filippakopoulos, M. E. Bunnage, S. Müller, S. Knapp,
C. J. Schofield, P. E. Brennan, J. Am. Chem. Soc. 2014, 136, 9308–9319.
[5] For isoxazole-azepines, see: a) V. S. Gehling, M. C. Hewitt, R. G. Vaswani,
Y. Leblanc, A. Cîté, C. G. Nasveschuk, A. M. Taylor, J.-C. Harmange, J. E.
Audia, E. Pardo, S. Joshi, P. Sandy, J. A. Mertz, R. J. Sims III, L. Bergeron,
B. M. Bryant, S. Bellon, F. Poy, H. Jayaram, R. Sankaranarayanan, S. Yella-
pantula, N. B. Srinivasamurthy, S. Birudukota, B. K. Albrecht, ACS Med.
Chem. Lett. 2013, 4, 835–840; b) J. W. Schneider, Z. Gao, S. Li, M. Farooqi,
in 9 % yield (3.7 mg, white solid) by using NMP/Cu(OAc) as catalyst
2
for 24 h (Table 3, entry 4). Eluant: hexane (R = 0.30), m.p. 85–86 °C
(
f
ref.[ 82–84 °C). See below for spectroscopic data.
68]
Hexadeca-7,9-diyne (31): From 1-octyne (46.1 mg) in 29 % yield
13.1 mg, clear oil) by using DABCO/Cu(OAc) as catalyst for 24 h.
[
(
2
1
3
Eluant: hexane/EtOAc = 4:1 (R = 0.83). C NMR (50 MHz, CDCl3):
f
δ = 14.0 (q, 2 C; 2 CH ), 19.2 (t, 2 C; 2 CH ), 22.5 (t, 2 C; 2 CH ), 28.4
3
2
2
[
(
t, 2 C; 2 CH ), 28.5 (t, 2 C; 2 CH ), 31.3 (t, 2 C; 2 CH ), 65.4 (s, 2 C; 2
2 2 2
C≡ C-CH ), 77.5 ppm (s, 2 C; 2 C≡ C-CH ).
2
2
1
,6-Di(pyrrolidin-1-yl)hexa-2,4-diyne-1,6-dione (32): From 1-
pyrrolidin-1-yl)prop-2-yn-1-one (52.2 mg) in 12 % yield (6.4 mg,
white solid) by using NMP/Cu(OAc) as catalyst for 24 h. Recovered
(
2
2
1.7 mg of 1-(pyrrolidin-1-yl)prop-2-yn-1-one (R = 0.40). Eluant:
f
hexane/EtOAc = 1:1 then hexane/EtOAc = 1:2 (R = 0.22), m.p. 105 °C
f
1
(
6
dec.). H NMR (CDCl ): δ = 1.87–2.00 (m, 4 H, 2 CH ), 3.48 (t, J =
3
2
13
.8 Hz, 2 H; CH N), 3.62 ppm (t, J = 6.8 Hz, 2 H; CH N). C NMR
2
2
(
7
CDCl ): δ = 24.5 (t; CH ), 25.3 (t; CH ), 45.7 (t; CH N), 47.9 (t; CH N),
3 2 2 2 2
+
1.0 (s; C≡ ), 74.9 (s; C≡ ), 150.4 ppm (s; CO). MS (ESI , MeOH): m/z
+
(%) = 267 (100) [M + Na] .
1,4-Diphenylbuta-1,3-diyne (30): Chloroform (2236 mg, 1.5 mL)
was added to nitropentane 1h (125.8 mg, 2.5 equiv.), copper acet-
ate (3.9 mg, 0.021 mmol), DABCO (47.1 mg. 0.420 mmol), and
phenylacetylene (44 mg, 0.430 mmol), and then the mixture was
Eur. J. Org. Chem. 0000, 0–0
www.eurjoc.org
11
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
T.-S. Tang, I. Bezprozvanny, D. E. Frantz, J. Hsieh, Nat. Chem. Biol. 2008,
, 408–410.
6] For 3-carbamoylisoxazoles, see: a) W. Tuo, N. Leleu-Chavain, A. Barczyk,
[17] For a recent example utilizing other starting materials, see: J. S. Oakdale,
R. K. Sit, V. V. Fokin, Chem. Eur. J. 2014, 20, 11101–11110.
[18] F. De Sarlo, F. Machetti, Condensation of Primary Nitro Compounds to
Isoxazole Derivatives: Stoichiometric to Catalytic, in: Methods and Applica-
tions of Cycloaddition Reactions in Organic Syntheses, Wiley, New York,
2014, p. 205–222.
[19] S. D. Nelson, D. J. Kasparian, W. F. Trager, J. Org. Chem. 1972, 37, 2686–
2688.
[20] E. Kaji, K. Harada, S. Zen, Chem. Pharm. Bull. 1978, 26, 3254–3256.
[21] K. Z. Harada, Chem. Pharm. Bull. 1980, 28, 3296–3303.
4
[
N. Renault, L. Lemaire, P. Chavatte, R. Millet, Bioorg. Med. Chem. Lett.
2016, 26, 2701–2705; b) P. A. Harris, B. W. King, D. Bandyopadhyay, S. B.
Berger, N. Campobasso, C. A. Capriotti, J. A. Cox, L. Dare, X. Dong, J. N.
Finger, L. C. Grady, S. J. Hoffman, J. U. Jeong, J. Kang, V. Kasparcova, A. S.
Lakdawala, R. Lehr, D. E. McNulty, R. Nagilla, M. T. Ouellette, C. S. Pao,
A. R. Rendina, M. C. Schaeffer, J. D. Summerfield, B. A. Swift, R. D. Totoritis,
P. Ward, A. Zhang, D. Zhang, R. W. Marquis, J. Bertin, P. J. Goughb, J. Med.
Chem. 2016, 59, 2163–2178; c) T. Meng, D. Zhang, Z. Xie, T. Yu, S. Wu, L.
Wyder, U. Regenass, K. Hilpert, M. Huang, M. Geng, J. Shen, J. Med. Chem.
[
22] Y. Basel, A. Hassner, Synthesis 1997, 309–312.
[
23] It has long been known that aliphatic and aromatic nitrile oxides dimer-
ize to furoxan, see: A. Werner, H. Buss, Ber. Dtsch. Chem. Ges. 1894, 27,
2
014, 57, 9832–9843.
7] For gaboxadol, see: a) P. Krogsgaard Larsen, Acta Chem. Scand. Sect. B
977, 31, 584–588; b) P. Krogsgaard Larsen, Nature 1977, 268, 53–55.
[
[
2
193–2201.
1
[
[
[
24] For the reversion of furoxans into nitrile oxides, see: D. R. Brittelli, G. A.
Boswell Jr., J. Org. Chem. 1981, 46, 316–320.
25] P. A. Wade, N. V. Amin, H.-K. Yen, D. T. Price, G. F. Huhn, J. Org. Chem.
8] For two specific best-selling drugs Leflunomide (Arava) and Sulpha-
methoxazole (Bactrim), see: M. Baumann, I. R. Baxendale, S. V. Ley, N.
Nikbin, Beilstein J. Org. Chem. 2011, 7, 442–495.
9] For Leflunomide (Arava) Sulphamethoxazole (Bactrim), see: a) G. Heu-
bach, G. Hoerlein, B. Sachse, Ger. Pat. DE2525023, 1975 [Chem. Abstr.
1
984, 49, 4595–4601.
26] T. Shimizu, Y. Hayashi, H. Shibafuchi, K. Teramura, Bull. Chem. Soc. Jpn.
986, 59, 2827–2831.
[
1
1
977, 86, 106569]; b) G. Bertolini, M. Aquino, M. Biffi, G. d'Atri, F. Di Pierro,
F. Ferrario, P. Mascagni, F. Somenzi, A. Zaliani, F. Leoni, J. Med. Chem.
997, 40, 2011–2016; c) A. Prakash, B. Jarvis, Drugs 1999, 58, 1137–1164.
[27] P. A. Harris, A. Jackson, J. A. Joule, Tetrahedron Lett. 1989, 30, 3193–3196.
[28] L. Cecchi, F. De Sarlo, F. Machetti, Eur. J. Org. Chem. 2006, 4852–4856.
[29] L. Guideri, F. De Sarlo, F. Machetti, Chem. Eur. J. 2013, 19, 665–677.
[30] F. Machetti, L. Cecchi, E. Trogu, F. De Sarlo, Eur. J. Org. Chem. 2007, 4352–
1
[
10] For isoxazolylpenicillins (Oxacillin), see: F. P. Doyle, A. A. W. Long, J. H. C.
Nayler, E. R. Stove, Nature 1961, 192, 1183–1184; F. P. Doyle, J. H. C.
Nayler, US2996501, 1961 [Chem. Abstr. 1962, 58, 31448]; for Flucloxacil-
lin, see: J. C. Hanson, A. A. W. Long, J. H. C. Nayler, E. R. Stove, J. Chem.
Soc. 1965, 5976–5983; for Dicloxacillin Cloxacillin, see: J. H. C. Nayler,
A. A. W. Long, D. M. Brown, P. Acred, G. N. Rolinson, F. R. Batchelor, S.
Stevens, R. Sutherland, Nature 1962, 195, 1264–1267; F. P. Doyle, J. H. C.
Nayler, Brit. Pat. GB905778, 1962 [Chem. Abstr. 1963, 58, 66517].
4
359.
[
31] Our synthetic procedure was repeated in other laboratories, see: a) Z.
Lian, S. D. Friis, T. Skrydstrup, Chem. Commun. 2015, 51, 3600–3603; b)
P. Das, A. O. Omollo, L. J. Sitole, E. McClendon, E. J. Valente, D. Raucher,
L. R. Walker, A. T. Hamme II, Tetrahedron Lett. 2015, 56, 1794–1797; c) G.
Shakya, H. Rivera Jr., D. J. Lee, M. J. Jaremko, J. J. La Clair, D. T. Fox, R. W.
Haushalter, A. J. Schaub, J. Bruegger, J. F. Barajas, A. R. White, P. Kaur,
E. R. Gwozdziowski, F. Wong, S.-C. Tsai, M. D. Burkart, J. Am. Chem. Soc.
[
11] For Zonisamide, see: a) H. Uno, M. Kurokawa, Chem. Pharm. Bull. 1978,
2
6, 3498–3503; b) H. Uno, M. Kurokawa, Y. Masuda, Ger. Offen.
2014, 136, 16792–16799; d) H. Mitsudera, K. Awasaguchi, T. Awano, K.
DE2825410, 1979 [Chem. Abs. 1980, 92, 128899]; c) H. Uno, M. Kuokawa,
Y. Masuda, H. Nishimara, J. Med. Chem. 1979, 22, 180–183.
Ujihara, WO2014119696, 2014 [Chem. Abstr. 2014, 161, 306272]; e) G.
Griffioen, T. Van Dooren, V. Rojas de La Palma, K. Shelley, A. Marchand,
S. Allasia, A. Kilonda, P. Chaltin, WO2010142801, 2010 [Chem. Abstr.
[
12] For Valdecoxib, see: a) J. J. Talley, D. L. Brown, J. S. Carter, M. J. Graneto,
C. M. Koboldt, J. L. Masferrer, W. E. Perkins, R. S. Rogers, A. F. Shaffer, Y. Y.
Zhang, B. S. Zweifel, K. Seibert, J. Med. Chem. 2000, 43, 775–777; b) J. J.
Talley, S. R. Bertenshaw, D. L. Brown, J. S. Carter, M. J. Graneto, M. S.
Kellogg, C. M. Koboldt, J. Yuan, Y. Y. Zhang, K. Seibert, J. Med. Chem.
2
011, 154, 64628]; f) G. Griffioen, T. Van Dooren, V. Rojas de La Palma,
K. Shelley, A. Marchand, S. Allasia, A. Kilonda, P. Chaltin, WO2010142801,
010 [Chem. Abstr. 2011, 154, 64628].
32] E. Trogu, C. Vinattieri, F. De Sarlo, F. Machetti, Chem. Eur. J. 2012, 18,
081–2093.
2
[
2
2
000, 43, 1661–1663; c) D. Ormrod, K. Wellington, A. J. Wagstaff, Drugs
002, 62, 2059–2071; d) I. Atukoralaa, D. J. Hunter, Expert Opin. Pharma-
2
[
[
33] J. Chau, S. Xu, M. A. Ciufolini, J. Org. Chem. 2013, 78, 11901–11910.
34] F. M. Cordero, D. Giomi, L. Lascialfari, Five-Membered Ring Systems with O
and N Atoms, in: Progress in Heterocyclic Chemistry (Eds.: G. W. Gribble,
J. A. Joule), Elsevier, Amsterdam, 2014, vol. 26, p. 319–348.
cother. 2013, 14, 1077–1086.
[
[
[
13] For Danazol, see: a) A. J. Manson, F. W. Stonner, H. C. Neumann, R. G.
Christiansen, R. L. Clarke, J. H. Ackerman, D. F. Page, J. W. Dean, D. K.
Phillips, G. O. Potts, A. Arnold, A. L. Beyler, R. O. Clinton, J. Med. Chem.
[35] M. P. Mower, D. G. Blackmond, J. Am. Chem. Soc. 2015, 137, 2386–2391.
[36] I. Yavari, M. Piltan, L. Moradi, Tetrahedron 2009, 65, 2067–2071.
[37] S. Sadegh-Samiei, I. Yavari, S. Skoulika, Helv. Chim. Acta 2015, 98, 589–
1963, 6, 1–9; b) D. Rosi, H. C. Neumann, R. G. Christiansen, H. P. Schane,
G. O. Potts, J. Med. Chem. 1977, 20, 349–352.
14] a) P. L. van der Peet, T. U. Connell, C. Gunawan, J. M. White, P. S. Donnelly,
S. J. Williams, J. Org. Chem. 2013, 78, 7298–7304; b) A. D. Burrows, C. G.
Frost, M. F. Mahon, P. R. Raithby, C. Richardson, A. J. Stevenson, Chem.
Commun. 2010, 46, 5064–5066; c) Y.-G. Lee, Y. Koyama, M. Yonekawa, T.
Takata, Macromolecules 2009, 42, 7709–7717.
15] For seminal reviews, see: a) A. Quilico, Isoxazoles and Related Compounds,
in: The Chemistry of Heterocyclic Compounds (Ed. A. Weissberger), Wiley,
New York, 1962, vol. 17, p. 1–233; b) Ch. Grundmann, P. Grünanger, The
Nitrile Oxides: Versatile Tools of Theoretical and Preparative Chemistry,
Springer, Berlin, 1971; c) P. Grünanger, P. Vita-Finzi, Isoxazoles, in: The
Chemistry of Heterocyclic Compounds (Eds.: E. C. Taylor, A. Weissberger),
Wiley, New York, 1991, vol. 49, part 1, p. 1–416; d) P. Grünanger, P. Vita-
Finzi, J. E. Dowling (Eds.), The Chemistry of Heterocyclic Compounds, Wiley,
New York, 1999, vol. 49, part 2.
16] For recent reviews, see: a) D. Giomi, F. M. Cordero, F. Machetti, Isoxazoles,
in: Comprehensive Heterocyclic Chemistry III (Ed.: A. R. Katritzky), Elsevier,
Oxford, UK, 2008, vol. 4, p. 365–486; b) A. M. S. Silva, A. C. Tome, T. M. V.
Pinho e Melo, J. Elguero, Five-Membered Heterocycles: 1,2-Azoles, part 2,
Isoxazoles and Isothiazoles, in: Modern Heterocyclic Chemistry (Eds.: J. Alva-
rez-Builla, J. J. Vaquero, J. Barluenga), Wiley-VCH, Weinheim, Germany,
5
92.
[
38] K.-i. Itoh, T. Aoyama, H. Satoh, Y. Fujii, H. Sakamaki, T. Takido, M. Kodo-
mari, Tetrahedron Lett. 2011, 52, 6892–6895.
[
[
[
[
39] L. Cecchi, F. De Sarlo, F. Machetti, Synlett 2007, 2451–2453.
40] L. Cecchi, F. De Sarlo, F. Machetti, Chem. Eur. J. 2008, 14, 7903–7912.
41] T. Gensch, F. Glorius, Science 2016, 352, 294–295.
42] a) E. Winterfeldt, Chem. Ber. 1964, 97, 1952–1958; b) R. M. Acheson, P. J.
Ansell, J. R. Murray, J. Chem. Res. Synop. 1986, 378–379; c) E. Wenkert,
K. A. H. Adams, C. L. Leicht, Can. J. Chem. 1963, 41, 1844–1846; d) M.
Medion-Simon, U. Pindur, Helv. Chim. Acta 1991, 74, 430–437.
43] We verified the dimerization of methyl propiolate in the presence of
DABCO or NMP; see the Exp. Section.
[
[
44] R. G. Pearson, D. H. Anderson, L. L. Alt, J. Am. Chem. Soc. 1955, 77, 527–
5
29.
[
[
[
45] S. Mo, P. Huang, J. Xu, Org. Biomol. Chem. 2014, 12, 4192–4200.
46] E. Trogu, L. Cecchi, F. De Sarlo, L. Guideri, F. Ponticelli, F. Machetti, Eur. J.
Org. Chem. 2009, 5971–5978.
[47] L. Cecchi, F. De Sarlo, C. Faggi, F. Machetti, Eur. J. Org. Chem. 2006, 3016–
3020.
2
011, p. 727–808; c) F. Hu, M. Szostak, Adv. Synth. Catal. 2015, 357, 2583–
[48] R. Zhang, J. Chen, Synthesis 1990, 817–819.
[49] See page 6894 in ref.[
38]
2614.
Eur. J. Org. Chem. 0000, 0–0
www.eurjoc.org
12
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
[
[
[
50] With 4-(dimethlyamino)pyridine, di-tert-butyl dicarbonate in acetonitrile,
[59] Although the reaction was performed under an inert atmosphere, the
reaction mixture was probably not completely bereft of dioxygen.
[60]
[
22]
see ref.
51] With sodium methylate, acetyl chloride in N,N-dimethylacetamide, see
For an interesting example of the use of CuII in a large excess amount
[
21]
ref.
under an inert atmosphere, see: R. Berscheid, F. Vögtle, Synthesis 1992,
52] Nitropropane reacted with phenylacetylene in very low yield (6 %) by
using ethyl chloroformate. A better yield (31 %) was obtained by using
5
8–62.
61] K. Balaraman, V. Kesavan, Synthesis 2010, 3461–3466.
62] G. Biagiotti, S. Cicchi, F. De Sarlo, F. Machetti, Eur. J. Org. Chem. 2014,
906–7915.
[
[
[
26]
benzenesulfonyl chloride, see ref.
A slightly better result (36 %) was
reported with the use of di-tert-butyl dicarbonate, see ref.[
53] a) C. Glaser, Ber. Dtsch. Chem. Ges. 1869, 2, 422–424; b) C. Glaser, Ann.
Chem. Pharm. 1870, 154, 137–171.
22]
7
[
[
[
[
63] C. B. Kanner, U. K. Pandit, Tetrahedron 1982, 38, 3597–3604.
[
64] G. S. King, P. D. Magnus, H. S. Rzepa, J. Chem. Soc. Perkin Trans. 1 1972,
54] a) A. S. Hay, J. Org. Chem. 1960, 25, 1275–1276; b) A. S. Hay, J. Org. Chem.
4
37–443.
65] L. K. Vagina, V. N. Chistokletov, A. A. Petrov, Zh. Org. Khim. 1966, 2, 417–
23 [J. Org. Chem. USSR 1966, 2, 414–420 (English Translation)].
1
962, 27, 3320–3321.
55] P. Siemsen, C. Livingston, F. Diederich, Angew. Chem. Int. Ed. 2000, 39,
632–2657; Angew. Chem. 2000, 112, 2740–2767.
[
4
2
[66] T. V. Hansen, P. Wu, V. V. Fokin, J. Org. Chem. 2005, 70, 7761–7764.
[67] F. Pünner, G. Hilt, Chem. Commun. 2012, 48, 3617–3619.
[68] O. A. Kuznetsova, E. F. Khmara, V. I. Filyakova, M. A. Uimin, A. E. Ermakov,
C. K. Rhee, V. N. Charushin, Zh. Obshch. Khim. 2007, 77, 439–443 [Russ.
J. Gen. Chem. 2007, 77, 404–408].
[
[
56] K. Balaraman, V. Kesavan, Synthesis 2010, 3461–3466.
57] For mechanist considerations on the use of copper(II) salts, see: G.
Eglinton, A. R. Galbraith, J. Chem. Soc. 1959, 889–896.
[
58] For other alkyne-based reactions that suffered from competition with
homocoupling, Sonogashira reaction, see: a) A. Elangovan, Y.-H. Wang,
T.-I. Ho, Org. Lett. 2003, 5, 1841–1844; for Cu-catalyzed Huisgen reaction,
see: b) V. D. Bock, H. Hiemstra, J. H. van Maarseveen, Eur. J. Org. Chem.
2006, 51–68; c) C. J. Duxbury, D. Cummins, A. Heise, J. Polym. Sci., Part
Received: July 20, 2016
A: Polym. Chem. 2009, 47, 3795–3802.
Published Online: ■
Eur. J. Org. Chem. 0000, 0–0
www.eurjoc.org
13
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
Synthetic Methods
A. Baglieri, L. Meschisi, F. De Sarlo,
F. Machetti* ...................................... 1–14
Competitive Copper Catalysis in the
Condensation of Primary Nitro Com-
pounds with Terminal Alkynes: Syn-
thesis of Isoxazoles
The combination of copper with a suit- amines, nitriles, esters, phosphates,
able base results in a good catalyst for and amides are prepared. Competitive
the condensation of nitro compounds processes of the alkynes and nitro
with alkynes to isoxazoles. 3,5-Disub- compounds alone or in their combina-
stituted isoxazoles bearing various tion are under control.
functional groups including alcohols,
DOI: 10.1002/ejoc.201600897
Eur. J. Org. Chem. 0000, 0–0
www.eurjoc.org
14
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim