Base- and copper-catalysed condensation of primary activated nitro compounds with enolisable compounds

Article abstract of DOI:10.1002/ejoc.200900802

Primary nitro compounds have not been employed as nitrile oxide precursors in reactions with active methylene compounds because the reagents commonly used as dehydrating agents also react with these dipolarophiles. However, the Cu ^II-catalysed

Full text of DOI:10.1002/ejoc.200900802

FULL PAPER
DOI: 10.1002/ejoc.200900802
Base- and Copper-Catalysed Condensation of Primary Activated Nitro
Compounds with Enolisable Compounds
Elena Trogu,[a] Luca Cecchi,[a] Francesco De Sarlo,*[a,b] Luca Guideri,[c] Fabio Ponticelli,[b,c]
and Fabrizio Machetti*[b,d]
Keywords: Nitro compounds / Isoxazoles / Organocatalysis / Copper / Enols
Primary nitro compounds have not been employed as nitrile
used. In the absence of added dipolarophiles, these nitro
oxide precursors in reactions with active methylene com- compounds underwent self-condensation to the correspond-
pounds because the reagents commonly used as dehydrating
agents also react with these dipolarophiles. However, the
CuII-catalysed cycloaddition/condensation procedure has
been shown to be viable with these substrates, leading di-
rectly to the expected polyfunctional isoxazoles provided ni-
tro compounds with enhanced acidity (“activated”) were
ing furoxans. However, as well as 3,4-dibenzoylfuroxan, ben-
zoylnitromethane predominantly gave the isomer 3-benzoyl-
4-nitro-5-phenylisoxazole, the structure of which was con-
firmed by crystallographic analysis.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2009)
primary nitro compounds as the starting materials. These
are dehydrated to nitrile oxides with various acylating rea-
gents such as aryl isocyanates,[8] acyl chlorides,[9] anhy-
Introduction
Active methylene compounds (those with two geminal
electron-withdrawing groups: β-diketones, β-keto esters, cy-
anoacetate, etc.) are known to react with hydroximoyl chlo-
rides in the presence of a base to give isoxazole deriva-
tives.[1] This area was first developed by Quilico and co-
workers in the 1930s.[2] They found that benzohydroximoyl
chloride reacts with β-diketones and other “active methyl-
ene” compounds only in the presence of base, producing
isoxazoles. This reaction was later recognised as taking
place via the intermediate nitrile oxide derived from the cor-
responding hydroximoyl chloride.[3] These procedures are
still in use today as a convenient approach to highly func-
tionalised isoxazoles, either from hydroximoyl chlorides[4,5]
or from isolated nitrile oxides.[6,7] In addition, another pro-
tocol is known to lead to isoxazoles and isoxazolines using
[11]
drides[10] and POCl3 among others.[12] In the presence of
dipolarophiles, the cycloaddition of nitrile oxide to double
or triple bonds leads to isoxazolines or isoxazoles, respec-
tively. However, this protocol has the disadvantage if ap-
plied to enolic dipolarophiles that the reagents commonly
used as dehydrating agents also react with these di-
polarophiles.[13–15] Therefore this approach to the direct
preparation of isoxazoles has been largely disregarded. To
the best of our knowledge there is only one report describ-
ing the treatment of dibenzoylmethane with an excess of
phenylnitromethane and acetyl chloride under basic condi-
tions to afford 4-benzoyl-3,5-diphenylisoxazole among
other products.[16] To overcome this difficulty, a procedure
has been proposed that involves the use of preformed pyr-
rolidine enamines of substituted β-keto esters[11b,17,18] or β-
diketones,[16,19] but this adds a further step to the whole
process.
The use of primary nitro compounds as precursors of
isoxazole derivatives has recently been improved. Nitro
compounds with enhanced acidity and dipolarophiles con-
dense to form the product by organocatalysis.[20–23] 1,4-Di-
azabicyclo[2.2.2]octane (DABCO) gives the best results if
used alone, but the reaction becomes faster on addition of
a CuII salt. With a CuII salt, other tertiary amines like tri-
ethylamine (TEA) or N-methylpiperidine (NMP) appear to
be more suitable and cycloaddition/condensation reactions
occur even with nitroalkanes.[24,25]
[a] Dipartimento di Chimica Organica “U. Schiff”, Università di
Firenze,
Via della Lastruccia 13, 50019 Sesto Fiorentino, Firenze, Italy
Fax: +39-055-4573531
E-mail: francesco.desarlo@unifi.it
[b] Centro Interuniversitario sulle Reazioni Pericicliche e Sintesi di
Sistemi Etero e Carbociclici (CIRP), c/o F. De Sarlo
Via della Lastruccia 13, 50019 Sesto Fiorentino, Firenze, Italy
http://www.unifi.it/cirp
[c] Dipartimento di Chimica, Università di Siena,
Via Aldo Moro 2, 53100 Siena, Italy
[d] Istituto di Chimica dei Composti Organometallici del CNR,
c/o Dipartimento di Chimica Organica “U. Schiff”, Università
di Firenze,
Via della Lastruccia 13, 50019 Sesto Fiorentino, Firenze, Italy
Fax: +39-055-4573531
E-mail: fabrizio.machetti@unifi.it
In this paper we report the application of this catalytic
procedure to “activated” primary nitro compounds using
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.200900802.
Eur. J. Org. Chem. 2009, 5971–5978
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
5971

F. De Sarlo, F. Machetti et al.
FULL PAPER
active methylene compounds as dipolarophiles. The reac- chloroform is still to be preferred. Thus, a CuII salt
tions of nitroalkanes with these dipolarophiles were unsuc- (0.1 equiv.) with NMP (0.2 equiv.) was employed as the cat-
cessful.
alyst system in chloroform for the reactions of 1a, 1b and
1c, but for 1d the reaction was performed in toluene.
1
The reaction in entry 3 of Table 1 was followed by H
NMR spectroscopy. Kinetic profiles, included in the Sup-
porting Information, were prepared by plotting the concen-
trations versus time of the product 5d and nitromethane,
formed by slow cleavage of benzoylnitromethane (1d): ni-
tromethane was produced together with benzoic acid, which
reacted with the basic catalyst and thus the rate dropped,
even in the presence of excess of the starting material 1d.
Ethyl nitroacetate (1a), methyl nitroacetate (1b), N-meth-
ylnitroacetamide (1c) and benzoylnitromethane (1d) with
acetylacetone (2), respectively, afforded the 4-acetylisox-
azoles 5a–d. Similarly, reactions of the nitroacetates 1a and
1b and the nitro ketone 1d with benzoylacetone (3) gave the
regioisomers 6a, 6b and 6d, respectively. Benzoylnitrometh-
ane (1d) and methyl nitroacetate (1b) also reacted with ethyl
acetoacetate (4) to give the isoxazoles 7d and 7b, respec-
tively.
Results and Discussion
By using the model reaction between benzoylnitrometh-
ane (1d) and acetylacetone (2) we investigated the optimal
conditions for isoxazole formation. The reaction was per-
formed with various catalyst compositions and solvents and
the spectroscopic yields observed after an established time
are reported in Table 1.
Table 1. Optimisation of the reaction conditions of the model reac-
tion between benzoylnitromethane (1d) and acetylacetone (2).[a]
The results are collected in Table 2: no other regioiso-
mers were identified in addition to the products 5–7 illus-
trated. The yields compare favourably with those of pre-
vious methods (last column), which, however, require an
additional step. Methyl nitroacetate (1b) was chosen to ob-
Entry
Solvent
Catalyst
Yield [%][b]
Base [equiv.]
CuII [equiv.]
1
2
3
4
5
6
7
8
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
C2H5OH
toluene
DABCO (0.2)
DABCO (0.2)
NMP (0.2)
NMP (0.1)
NMP (0.2)
NMP (0.1)
DABCO (0.1)
DABCO (0.1)
NMP (0.2)
NMP (0.2)
NMI[g] (0.2)
TEA (0.2)
–
0.1[c]
–
53 (62)
trace (4)
73 (73)
57 (67)
6 (6)
14 (20)
51 (58)
6 (6)
0.1[c]
0.05[c]
–
1
tain simpler H NMR spectra of the crude mixtures. How-
ever, it turned out that these reactions gave better results
than those of the ethyl ester (compare entries 1 and 2, 5
and 6). Thus, methyl nitroacetate is to be preferred for the
preparation of isoxazoles bearing a carboxylate function-
ality at C-3. The isoxazole 6b was obtained selectively from
four possible isomers. The structure of 6b was assigned by
combined 13C NMR and long-range C–H correlation
(gHMBC) NMR analysis.[31] In a previous cycloaddition
procedure this isomer was isolated as a minor product
–
0.05[c]
–
9
0.1[d]
0.1[c] (1.1)[e]
0.1[c]
0.1[c]
0.1
54 (62)
10
11
12
13
14
15
85[f]
12 (18)
49 (50)
0
trace
78 (90)
NMP (0.2)
NMP (0.2)
0.1[c]
0.1[c]
[a] Performed at 60 °C, see Exp. Sect. for detailed reaction condi- (29%) along with 4-acetyl-3-ethoxycarbonyl-5-phenylisox-
azole (43%).[27]
tions. [b] Spectroscopic yields evaluated by NMR after 18 h. The
spectroscopic yields after 42 h are given in parentheses (but after
This double condensation reaction catalysed by cop-
72 h for entry 15). [c] Cu(AcO)2. [d] Cu(acac)2. [e] Cu(acac)2
instead of acetylacetone. [f] Possibly an excessive value owing to
signal broadening caused by a high copper concentration. [g] N-
per(II) was found to proceed smoothly with β-diketones,
whereas for ethyl acetoacetate (4) the conversions (entries 8
and 9) observed by H NMR were less than 30%. Even by
1
Methylimidazole.
raising the reaction temperature or prolonging the reaction
The use of base alone as the catalyst was unsatisfactory time the ethyl acetoacetate did not react further. Neither
as poor yields of the expected isoxazole 5d were obtained changing the solvent (toluene instead of chloroform) nor
(entries 2, 5, 6 and 8). Higher isoxazole yields were obtained the addition of further nitro compound and catalyst in-
on addition of copper(II) to the base (entries 1, 3, 4 and 7). creased the conversion. Substoichiometric addition of a sec-
The best results were achieved with a catalyst loading of ond base, such as pyrrolidine, only slightly increased the
20% base and 10% copper(II) (cf. entries 3 and 4). Of the yields.
bases explored, N-methylpiperidine (NMP) is to be pre-
In addition to the reported isoxazole derivatives 5–7, in
ferred (cf. entries 1, 3, 11 and 12). Similar results were ob- the reactions of 1a, 1b and 1d, the furoxans 8a, 8b and
tained by using copper(II) acetylacetonate instead of cop- 8d, respectively, were detected. In the presence of base and
per(II) acetate (entry 9) or acetylacetone (entry 10). No moisture, heating at 60 °C caused the cleavage of all these
isoxazole 5d was produced in the presence of copper(II) compounds to some extent, depending on the concentration
alone (entry 13). The use of other solvents showed that a of the base.[32] For this reason we were unable to detect the
protic solvent (ethanol, entry 14) was not suitable, whereas furoxan 8a in our previous experiments[20] on reactions of
in toluene the model reaction gave an excellent result 1a with other dipolarophiles and DABCO (0.2 equiv.). The
(entry 15). However, for other substrates (nitroacetates) reaction conditions reported herein (0.08 equiv. NMP) have
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Eur. J. Org. Chem. 2009, 5971–5978

Catalysed Condensation of Activated Nitro Compounds
Table 2. Substituted isoxazoles from nitro compounds 1a–d and appropriate hydroximoyl chloride and triethylamine:[35] the
1,3-dicarbonyl compounds 2–4.[a]
melting point of 100–101 °C and the IR absorption at
1680 cm–1 are in agreement with the properties of 9.
Figure 2. X-ray crystal structure of 9.
Entry
R
R1
Product
Yield [%]
Lit.
We submitted samples of 8d and 9 to prolonged treat-
ment under the reaction conditions, thus verifying that the
two isomers do not interconvert. When benzoylnitrometh-
ane (1d) alone was treated with the catalyst, both self-con-
densation products were obtained: the rate of self-conden-
sation and the molar ratios depend on the composition and
concentration of the catalyst (Table 3).
Exp.[b]
1
2
3
4
5
6
7
8
9
OEt
OMe
NHMe
Ph
OEt
OMe
Ph
Me
Me
Me
Me
Ph
Ph
Ph
5a
5b
5c
5d
6a
6b
6d
7b
7d
48
66
44[c,d]
30[e]
–
35 (41)[f]
85
–
65 (82)[f]
32[d,g]
29[e,h]
–
75
93
29
25
OMe
Ph
OEt
OEt
25[e]
32[d,i]
Table 3. Benzoylnitromethane self-condensation.[a]
[a] See the Exp. Sect. for details. [b] Isolated yields were determined
for the analytically pure product and are based on the dipolaroph-
ile. [c] Ref.[26] [d] The yield includes preparation of the dipole pre-
cursor. [e] Ref.[27] [f] The yield considering the recovered diketone
is given in parentheses. [g] Ref.[28,29] [h] Another isomer was also
present in 43% yield. [i] Ref.[28,30]
Entry
Catalyst
Base [mmol-%]
1d/8d/9[b]
CuII [mmol-%]
allowed the furoxans to be detected. In the absence of other
dipolarophiles, fair yields of the furoxans 8a (43%) and 8b
(68%) were obtained. This procedure appears to be conve-
nient and of synthetic interest in comparison with the
known preparation methods of these compounds.[33,34]
In the reactions of the nitro ketone 1d, an isomer of the
furoxan 8d (Figure 1) was detected and identified as 3-ben-
zoyl-4-nitro-5-phenylisoxazole (9) on the basis of spectral
evidence and crystallographic analysis. Compound 9 was
carefully analysed by NMR spectroscopy and distinguished
from the isomer 8d mainly on the basis of the 13C NMR
chemical shifts and long-range C–H connectivity (gHMBC)
experiments (Figure 1).
1
2
3
4
5
6
7
DABCO (4)
DABCO (4)
NMP (4)
2
–
2
–
4
–
4
0:37:63
8:30:62
0:61:39
42:30:28
0:0:100
11:0:89
0:34:66
NMP (4)
DABCO (8)
DABCO (8)
NMP (8)
[a] Reaction conditions: 18 h, 60 °C, CDCl3. See Exp. Sect. for
more details. [b] Molar ratios evaluated by NMR spectroscopy.
After 18 h, no residual 1d was observed if CuII was pres-
ent: the reactions were slower in the presence of only base.
However, the overall yields of the self-condensation prod-
ucts 8d and 9 were far from quantitative, considerable
amounts of benzoic acid and nitromethane being identified
in the 1H NMR spectra of the crude reaction mixtures.
Moreover, benzoic acid was found in molar excess with re-
spect to nitromethane because it originates from cleavage
of not only 1d but of the furoxan 8d as well.
The presence of the furoxans 8a, 8b and 8d indicates the
formation of their precursors, the corresponding nitrile ox-
ides 10a, 10b and 10d, produced by catalytic dehydration of
the nitro compounds 1a, 1b and 1d, respectively (Scheme 1).
This view is strongly supported by a theoretical study.[36]
The nitro ketone 1d in its enolic form behaves as a di-
polarophile like the other enolisable compounds 2–4, af-
Figure 1. Structures of the self-condensation products and key
NMR assignments of the quaternary carbon atoms in 8d and 9
based on long-range 13C–1H correlations.
The crystal structure of 9 is shown in the ORTEP dia- fording the nitroisoxazole 9[37] either via the nitrile oxide
gram in Figure 2. The same compound has previously been 10d or by the catalytic cycloaddition/condensation process
obtained by reaction of benzoylnitromethane (1d) with the we reported for other dipolarophiles.[20,25] No 4-nitroisox-
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F. De Sarlo, F. Machetti et al.
FULL PAPER
(chemical ionisation, CH4) mass spectra were obtained using a Shi-
madzu QP5050A quadrupole-based mass spectrometer (direct in-
troduction unless otherwise stated). Ion mass/charge ratios (m/z)
are reported as values in atomic mass units followed in parentheses
by the intensities relative to the base peak. IR spectra were re-
corded with a Perkin–Elmer 881 spectrometer. Elemental analyses
were obtained with an Perkin–Elmer 240C Elemental Analyser. All
compounds were named by using Autonom® (Beilstein Infor-
mation Systems) and modified where appropriate. Commercially
available (Lancaster and Aldrich) nitroacetates (1a and 1b), benzo-
ylnitromethane (1d), organic bases and enolisable compounds 2–4
were used as supplied. CHCl3 (ethanol free) was filtered through
a short pad of potassium carbonate just before use. N-Methyl-2-
nitroacetamide (1c) was prepared according to a reported pro-
cedure.[21]
azoles analogous to 9 were found in addition to the furox-
ans 8a,b: the weaker enolic character of the nitroacetates 1a
and 1b explains why cycloaddition leading to 4-nitroisox-
azoles is not observed.
Optimisation of Isoxazole Formation from Acetylacetone and Benzo-
ylnitromethane: See Table 1 for the most significant results; various
catalytic systems were screened in different solvents. The spectro-
scopic yields reported in Table 1 refer to reactions performed in an
apparatus in which eight reactions were carried out simultaneously.
Benzoylnitromethane (1d; 1.06 mmol), acetylacetone (2) or cop-
per(II) acetylacetonate for entry 10 (0.424 mmol) and dimethyl sul-
fone (Me2SO2) (10–13 mg, 0.106–0.138 mmol) as internal standard
were added to the catalyst [base (0.0848 or 0.0424 mmol, 0.2 and
0.1 equiv. respectively) or base (0.0848 or 0.0424 mmol) and cop-
per(II) acetate or copper(II) acetylacetonate for entry 9 (0.0424 or
0.0212 mmol, 0.1 and 0.05 equiv. respectively)] and the mixture dis-
solved in the indicated solvent (1.4 mL). The mixture was kept at
60 °C. After 18 and 42 h, a portion was withdrawn from the reac-
Scheme 1. Self-condensation of activated nitro compounds.
Conclusions
This study was aimed at the method, rather than at spe-
cific targets: only some of the many possible substrates have
been reported as selected examples. Functionalised 5-meth-
ylisoxazoles were regioselectively obtained by water release
using the convenient and economic Cu(OAc)2/NMP cata-
lytic system, thus avoiding the preliminary synthesis of hy-
droximoyl chlorides.
In addition to the mechanism illustrated in our previous
papers,[20] the cycloaddition/condensation process for “acti-
vated” primary nitro compounds might even take place, at
least in part, via intermediate nitrile oxides because the cor-
responding dimer furoxans are produced in the absence of
dipolarophiles. The nitroalkanes react with other di-
polarophiles only in the presence of the CuII/base catalyst
system and no furoxans have been detected so far. The cata-
lytic conversion of primary nitro compounds to furoxans
will be the subject of more detailed studies.
1
tion mixture, diluted with CDCl3 (0.6 mL) and the H NMR spec-
trum recorded. Integration of the methyl proton signal (singlet at
δ = 2.99 ppm, 6 H) of the internal standard and the acetyl protons
of isoxazole 5d (singlet at δ = 2.75 ppm, 3 H) gave the spectroscopic
yields. The evaluations of the conversions were unreliable and the
values are not reported. In the case of an unclear result, a duplicate
experiment was run.
Effect of Different Catalyst Compositions on Benzoylnitromethane
Self-Condensation Products: See Table 3 for the most significant re-
sults; different catalytic systems were screened by using the same
apparatus as above.
Copper and Base: Copper(II) acetate (0.021 or 0.042 mmol) was
Experimental Section
added to
a solution of benzoylnitromethane (1d; 176 mg,
1.06 mmol, 0.76 ) and base (0.042 or 0.084 mmol; 0.03 and
0.06 , respectively) in CDCl3 (1.4 mL) and the mixture magneti-
cally stirred in a sealed vessel at 60 °C. After 18 h the molar ratio
1d/8d[38]/9 was evaluated by 13C NMR (see later).
General Methods: Melting points were determined in capillaries
with a Büchi 510 apparatus and are uncorrected. Chromatographic
separations (column) were performed on silica gel 60 (40–6.3 µm)
with analytical grade solvents driven by a positive pressure of air;
Rf values refer to TLC (visualised with UV light and/or by dipping
the plates into a solution of permanganate or anisaldehyde fol-
lowed by heating with a heat gun) carried out on alumina-backed
plates coated with 25 mm silica gel (Merck F254) and the same
eluent as indicated for column chromatography. Solvent was re-
moved by evaporation on a rotary evaporator at room temperature.
1H and 13C NMR spectra were recorded with a Varian Mer-
curyplus 400 spectrometer (operating at 400 MHz for 1H NMR
and 100.58 MHz for 13C NMR) unless otherwise stated. The 1H
NMR spectroscopic data are reported as follows: s = singlet, d =
doublet, t = triplet, m = multiplet or unresolved, br. = broad signal,
Base: A solution of benzoylnitromethane (1d) (176 mg, 1.06 mmol,
0.76 ) and base (0.042 or 0.084 mmol; 0.03 or 0.06 , respectively)
in CDCl3 (1.4 mL) was magnetically stirred in a sealed vessel at
60 °C. After 18 h the molar ratio 1d/8d/9 was evaluated by 13C
NMR (see later).
Evaluation of the Molar Ratio: A solution of weighed amounts of
compounds 1d, 8d and 9 was prepared, the 13C NMR spectrum
(standard 13C experiment, 100.57 MHz, d1 = 1 s, CDCl3) recorded
and the intensity of selected signals at δ = 186.1 (1d), 181.4 (8d)
and 183.5 ppm (9) were compared. Thus the expected molar ratios
were obtained with a correction factor of 1.16 for 8d and this was
then applied to evaluate molar ratios from spectra recorded under
the same conditions.
coupling constant(s) in Hz, integration]. The multiplicity of the 13
C
NMR signals and their assignments were determined by gHMQC
and gHMBC experiments. Chemical shifts were determined relative
to the residual solvent peak (CHCl3: 7.24 ppm for 1H NMR and
77.0 ppm for 13C NMR). EI (electron impact, 70 eV) and CI
Experiments Exploring the Stability of 8d and 9 under the Reaction
Conditions: Compounds 8d and 9 were submitted to several experi-
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Catalysed Condensation of Activated Nitro Compounds
ments to establish whether they interconvert or transform into
other compounds. Experiments were performed in a septum-sealed
5-mm NMR tube, heating the reaction mixture (0.7 mL, CDCl3) at
60 °C for 18 h in the presence of Me2SO2 as the internal standard,
and analysed by NMR spectroscopy. Benzoic acid was also iden-
tified by MS.
4-Acetyl-N,5-dimethylisoxazole-3-carboxamide (5c): Treatment of 2
(43 mg) with 1c (125 mg) according to the general procedure gave
unreacted 2 (Rf = 0.68, 6 mg) and 5c (white solid, Rf = 0.28, 27 mg,
35%) after 38 h (CHCl3) and chromatographic purification (elution
first with hexane and then with hexane/diethyl ether, 2:5). The yield
based on recovered 2 was 41%; m.p. 108–109 °C (colourless need-
les, crystallised from diisopropyl ether). 1H NMR: δ = 2.56 (s, 3 H,
COCH3), 2.62 (s, 3 H, CH3C-5), 3.00 (d, J = 4.8 Hz, 3 H,
CONCH3), 6.85 (br. s, 1 H, NH) ppm. 13C NMR: δ = 13.3 (q,
CH3C-5), 26.4 (q, NCH3), 31.1 (q, COCH3), 116.8 (s, C-4), 156.1
(s, C-3), 159.6 (s, CONMe), 175.3 (s, C-5), 193.3 (s, COMe) ppm.
MS (EI): m/z (%) = 182 (14) [M]+, 167 (4), 152 (1), 139 (3), 125
Experiment a: A solution of 8d (12 mg, 0.039 mmol, 0.06 ), NMP
(3 µL, 0.021 mmol, 0.03 ) and Cu(AcO)2 (1.95 mg, 0.011 mmol,
0.015 ) showed by spectroscopic analysis a partial decomposition
of 8d in benzoic acid.
Experiment b: A solution of 8d (11 mg, 0.037 mmol, 0.05 ),
DABCO (2.2 mg, 0.020 mmol, 0.03 ) and Me2SO2 (4 mg,
0.042 mmol) showed by spectroscopic analysis a partial decomposi-
tion of 8d in benzoic acid.
(10), 111 (5), 83 (8), 58 (100) [CONHMe]+. IR (CDCl ): ν 3438,
˜
3
1689 (C=O), 1573, 1545, 1457, 1415 cm–1. C8H10N2O3 (182.18):
calcd. C 52.74, H 5.53, N 15.38; found C 52.76, H 5.82, N 15.69.
Experiment c: A solution of 8d (5.6 mg, 0.019 mmol), 9 (5.7 mg,
0.019 mmol) and Me2SO2 (3.5 mg, 0.037 mmol) showed by spectro-
scopic analysis a partial transformation in benzoic acid. No in-
terconversion between 8d and 9 was observed.
1-(3-Benzoyl-5-methylisoxazol-4-yl)ethanone (5d): Treatment of 2
(43 mg) with 1d (175 mg) according to the general procedure gave
5d (62 mg, 64%) as a colourless oil after 72 h (CHCl3) and chroma-
tographic purification (elution with hexane/AcOEt, 6:1; Rf = 0.31).
The same reaction carried out in toluene as above, after column
chromatography on silica gel (hexane/diethyl ether/triethylamine
15:1:1, Rf 0.21), gave the pure compound as a yellowish oil (82 mg,
Experiment d: A solution of 9 (35 mg, 0.119 mmol, 0.17 ),
DABCO (4.7 mg, 0.042 mmol, 0.06 ) and Me2SO2 (4 mg,
0.042 mmol) showed by 1H and 13C NMR neither conversion to
compound 8d nor transformation into other compounds.
1
85%). H NMR: δ = 2.32 (s, 3 H, CH3CO), 2.75 (s, 3 H, CH3C-
5), 7.48–7.53 (m, 2 H, Ph-Hmeta), 7.63–7.68 (m, 1 H, Ph-Hpara),
7.99–8.03 (m, 2 H, Ph-Hortho) ppm. 13C NMR: δ = 13.4 (q, CH3C-
5), 30.2 (q, CH3CO), 117.5 (s, C-4), 128.9 (d, 2 C, Ph-Cmeta), 130.3
(d, 2 C, Ph-Cortho), 134.8 (d, Ph-Cpara), 135.6 (s, Ph-Cipso), 159.6 (s,
C-3), 174.5 (s, C-5), 187.5 (s, COPh), 191.6 (s, COMe) ppm. MS
(EI): m/z (%) = 229 (Ͻ1) [M]+, 228 (Ͻ1), 199 (14) [M – Me]+, 105
Experiment e: A solution of 9 (35 mg, 0.119 mmol, 0.17 ), NMP
(5 µL, 0.042 mmol, 0.06 ), Cu(AcO)2 (3.8 mg, 0.021 mmol,
1
0.03 ) and Me2SO2 (5.2 mg, 0.055 mmol) showed by H and 13C
NMR neither conversion to compound 8d nor transformation into
other compounds.
General Procedure for the Preparation of Isoxazoles 5–7: The nitro
compound (1.06 mmol), dipolarophile (0.424 mmol) and NMP
(10 µL, 0.08 mmol) were added in sequence to a suspension of
Cu(OAc)2 (7.8 mg, 0.042 mmol) in the indicated solvent (1.4 mL).
The stirred mixture was heated in a sealed tube at 60 °C and stirred
for the indicated time. The solvent was then removed under vacuum
and the crude material was purified by column chromatography on
silica gel with the indicated eluent.
(100) [PhCO]+, 77 (55) [Ph]+, 51 (30). IR (CDCl ): ν 3069, 1684
˜
3
(C=O), 1598, 1572, 1457, 1418, 1218 cm–1. C13H11NO3 (229.23):
calcd. C 68.11, H 4.84, N 6.11; found C 67.89, H 5.18, N 6.28.
Ethyl 4-Benzoyl-5-methylisoxazole-3-carboxylate (6a): Treatment of
3 (69 mg) with 1a (141 mg) according to the general procedure gave
unreacted 3 (Rf = 0.50, 15 mg) and 6a (colourless oil, Rf = 0.39,
71 mg, 65%) as a colourless oil after 72 h (CHCl3) and chromato-
graphic purification (elution with hexane/ethyl acetate/Et3N,
Ethyl 4-Acetyl-5-methylisoxazole-3-carboxylate (5a): Treatment of
2 (43 mg) with 1a (141 mg) according to the general procedure gave
5a (40 mg, 48%) as a colourless oil after 72 h (CHCl3) and chroma-
tographic purification (elution with hexane/AcOEt, 5:1; Rf = 0.22).
1H NMR: δ = 1.39 (t, J = 7.2 Hz, 3 H, OCH2CH3), 2.46 (s, 3 H,
CH3CO), 2.63 (s, 3 H, CH3C-5), 4.44 (q, J = 7.2 Hz, 2 H,
OCH2CH3) ppm.[27] 13C NMR: δ = 13.2 (q, CH3C-5), 13.9 (q,
OCH2CH3), 30.4 (q, COCH3), 62.9 (t, OCH2CH3), 117.0 (s, C-4),
154.3 (s, C-3), 160.4 (s, CO2Et), 174.6 (s, C-5), 192.0 (s,
COMe) ppm. MS (EI): m/z (%) = 197 (100) [M]+, 182 (62) [M –
Me]+, 169 (32), 168 (6) [M – Et]+, 154 (24), 152 (34), 151 (71), 110
1
10:1:1). The yield based on recovered 3 was 82 %. H NMR: δ =
1.03 (t, J = 6.8 Hz, 3 H, OCH2CH3), 2.52 (s, 3 H, CH3C-5), 4.08
(q, J = 6.8 Hz, 2 H, OCH2CH3), 7.41–7.48 (m, 2 H, Ph-Hmeta),
7.56–7.61 (m, 1 H, Ph-Hpara), 7.72–7.75 (m, 2 H, Ph-Hortho) ppm.
13C NMR: δ = 12.2 (q, CH3C-5), 13.5 (q, OCH2CH3), 62.4 (t,
OCH2CH3), 116.1 (s, C-4), 128.7 (d, 2 C, Ph-Cmeta), 128.9 (d, 2 C,
Ph-Cortho), 133.6 (d, Ph-Cpara), 137.7 (s, Ph-Cipso), 155.0 (s, C-3),
159.2 (s, CO2Et), 173.1 (s, C-5), 188.2 (s, COPh) ppm. MS (EI):
m/z (%) = 259 (25) [M]+, 186 (42) [M – CO2Et]+, 105 (100),
[PhCO]+, 77 (57) [Ph]+, 51 (32). IR (CDCl ): ν 3067, 2985, 1740
˜
3
(C=O), 1664 (C=O), 1599, 1449, 1322, 1214 cm–1. C14H13NO4
(259.27): calcd. C 64.86, H 5.05, N 5.40; found C 64.62, H 5.27, N
5.01.
(20), 96 (19), 83 (39), 68 (79). IR (CDCl ): ν = 1739 (C=O), 1685
˜
3
(C=O), 1568, 1308, 1208 cm–1. C9H11NO4 (197.19): calcd. C 54.82,
H 5.62, N 7.10; found C 54.76, H 5.79, N 6.94.
Methyl 4-Acetyl-5-methylisoxazole-3-carboxylate (5b): Treatment
of 2 (43 mg) with 1b (126 mg) according to the general procedure
gave 5b (51 mg, 66%) as a colourless oil after 72 h (CHCl3) and
Methyl 4-Benzoyl-5-methylisoxazole-3-carboxylate (6b): Treatment
of 3 (69 mg) with 1b (126 mg) according to the general procedure
gave 6b (78 mg, 75%) as a white powder after 72 h (CHCl3) and
chromatographic purification (elution with hexane/diethyl ether/
chromatographic purification (elution with hexane/AcOEt, 5:1; Rf
1
= 0.16). H NMR: δ = 2.47 (s, 3 H, COCH3), 2.64 (s, 3 H, CH3C- Et3N, 10:1:1; Rf = 0.23); m.p. 86–88 °C (ref.[27] 82–85 °C, ethanol).
5), 3.98 (s, 3 H, CO2CH3) ppm. 13C NMR: δ = 13.2 (q, CH3C-5),
30.4 (q, COCH3), 53.4 (q, OCH3), 117.2 (s, C-4), 154.0 (s, C-3),
160.8 (s, CO2Me), 174.8 (s, C-5), 192.1 (s, COMe) ppm. MS (EI):
m/z (%) = 183 (34) [M]+, 168 (36) [M – Me]+, 151 (34), 124 (4), 82
1H NMR: δ = 2.52 (s, 3 H, CH3C-5), 3.65 (s, 3 H, OCH3), 7.43–
7.50 (m, 2 H, Ph-Hmeta), 7.56–7.62 (m, 1 H, Ph-Hpara), 7.70–7.76
(m, 2 H, Ph-Hortho) ppm. 13C NMR: δ = 12.3 (q, CH3C-5), 52.9 (q,
OCH3), 116.3 (s, C-4), 128.8 (d, 2 C, Ph-Cmeta), 128.9 (d, 2 C, Ph-
Cortho), 133.7 (d, Ph-Cpara), 137.6 (s, Ph-Cipso), 154.8 (s, C-3), 159.7
(s, CO2Me), 173.0 (s, C-5), 188.1 (s, COPh) ppm. MS (EI): m/z (%)
= 245 (16) [M]+, 244 (14), 230 (1), 200 (6), 186 (16) [M –
(19), 59 (100) [CO Me]+. IR (CDCl ): ν = 2957, 1744 (C=O), 1686
˜
2
3
(C=O), 1628, 1575, 1457, 1310, 1217 cm–1. C8H9NO4 (183.16):
calcd. C 52.46, H 4.95, N 7.65; found C 52.20, H 4.98, N 7.61.
Eur. J. Org. Chem. 2009, 5971–5978
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5975

F. De Sarlo, F. Machetti et al.
FULL PAPER
CO2Me]+, 105 (62), [PhCO]+, 77 (60) [Ph]+, 59 (62) [CO2Me]+, 51
with hexane/diethyl ether/triethylamine/MeOH (15:1:1:1) to afford
triethylammonium benzoate (119 mg, 0.721 mmol).
(34), 43 (100) [COMe]+. IR (CDCl ): ν = 3067, 2957, 1745 (C=O),
˜
3
1664 (C=O), 1600, 1450, 1323, 1221 cm–1. C13H11NO4 (245.23):
9: M.p. 100–101 °C (ref.[35] 100–101 °C, from methanol). 1H NMR:
δ = 7.52–7.62 (m, 4 H, Ph-Hmeta), 7.64–7.72 (m, 2 H, Ph-Hpara),
7.98–8.02 (m, 2 H, Ph-Hortho on C-5), 8.02–8.06 (m, 2 H, Ph-Hortho
on C-3) ppm. 13C NMR: δ = 123.7 (s), 129.0 (d, 2 C, Ph-Cmeta),
129.1 (d, 2 C, Ph-Cmeta), 129.4 (d, 2 C, Ph-Cortho on C-5), 130.1 [d,
2 C, C(O)-Ph-Cortho], 133.4 (d, Ph-Cpara on C-5), 134.8 (s), 135.2
[d, C(O)Ph-Cpara], 156.9 (s, C-3), 167.9 (s, C-5), 183.5 (s,
COPh) ppm. One carbon atom was not detected. MS (EI): m/z
(%)[40] = 147 (10) [PhC(O)CϵN–O]+, 131 (34) [PhC(O)CϵN]+, 105
calcd. C 63.67, H 4.52, N 5.71; found C 63.86, H 4.78, N 5.62.
(4-Benzoyl-5-methylisoxazol-3-yl)phenylmethanone (6d): Treatment
of 3 (69 mg) with 1d (175 mg) according to the general procedure
gave 6d (113 mg, 93%) as a colourless oil[39] after 40 h (toluene)
and chromatographic purification (elution with hexane/diethyl
1
ether/Et3N, 10:1:1; Rf = 0.27). H NMR: δ = 2.56 (s, 3 H, CH3C-
5), 7.31–7.37 (m, 2 H, Ph-H), 7.41–7.47 (m, 2 H, Ph-H), 7.47–7.53
(m, 1 H, Ph-H), 7.57–7.63 (m, 1 H, Ph-Hpara), 7.64–7.69 (m, 2 H,
Ph-Hortho on C-4), 7.99 (m, 1 H, Ph-Hortho on C-3), 8.01 (m, 1 H,
Ph-Hortho on C-3) ppm. 13C NMR: δ = 12.5 (q, CH3C-5), 117.1 (s,
C-4), 128.6 (d, 4 C, Ph-C), 128.8 (d, 2 C, Ph-C), 130.2 (d, 2 C, Ph-
Cortho on C-3), 133.4 (d, Ph-C on C-4), 134.3 (d, Ph-Cpara on C-3),
135.4 (s, Ph-C), 137.5 (s, Ph-C), 160.7 (s, C-3), 172.4 (s, C-5), 185.4
(s, COC-4), 188.1 (s, COC-3) ppm. MS (EI): m/z (%) = 291 (Ͻ1)
(100) [PhCO]+, 77 (80) [Ph]+, 51 (38). IR (CDCl ): ν = 3069, 1687
˜
3
(C=O), 1600, 1575, 1527, 1468, 1360, 1265, 1233 cm–1. C16H10N2O4
(294.26): calcd. C 65.31, H 3.43, N 9.52; found C 65.04, H 3.76, N
9.63.
Triethylammonium Benzoate: 1H NMR (200 MHz): δ = 1.29 (t, J
= 6.0 Hz, 3 H, CH3CH2), 3.14 (q, J = 6.0 Hz, 3 H, CH3CH2), 6.77
(br. s, 1 H, NH), 7.42–7.52 (m, 3 H, Ph-H), 7.85 –8.20 (m, 2 H,
Ph-H) ppm.
[M]+, 105 (100), [PhCO]+, 77 (58) [Ph]+, 51 (30). IR (CDCl ): ν =
˜
3
3067, 1670 (C=O), 1599, 1450, 1323, 1218 cm–1. C18H13NO3
(291.31): calcd. C 74.22, H 4.50, N 4.81; found C 74.24, H 4.57, N
4.88.
Diethyl 1,2,5-Oxadiazole-3,4-dicarboxylate 2-Oxide (8a): Cop-
per(II) acetate (22 mg, 0.12 mmol) was added to a mixture of ethyl
nitroacetate (1a; 399 mg, 3.0 mmol) and 1-methylpiperidine (24 mg,
0.24 mmol) in chloroform (2 mL) and the mixture was magnetically
stirred in a sealed vessel at 60 °C. After 96 h the reaction mixture
was diluted in chloroform (25 mL) and washed with H2O
(2ϫ20 mL), 0.05  NaOH (3ϫ20 mL) and H2O (3ϫ20 mL). The
organic layer was dried with Na2SO4 and filtered. The chloroform
was removed under vacuum to give the furoxan 8a as a pale-yellow
oil (0.15 g, 43% yield). An analytical sample was obtained as a
colourless oil by using a sublimator at 0.4 Torr and 60 °C. 1H
NMR: δ = 1.36 (t, J = 7.2 Hz, 3 H, CO2CH2CH3), 1.40 (t, J =
4-Ethyl 3-Methyl 5-Methylisoxazole-3,4-dicarboxylate (7b): Treat-
ment of 4 (55 mg) with 1b (126 mg) according to the general pro-
cedure gave 7b (26 mg, 29%) as a colourless oil after 72 h (CHCl3)
and chromatographic purification (elution with hexane/diethyl
ether, 5:1; Rf = 0.22). 1H NMR: δ = 1.31 (t, J = 7.2 Hz, 3 H,
CH2CH3), 2.67 (s, 3 H, CH3C-5), 3.95 (s, 3 H, OCH3), 4.28 (q, J
= 7.2 Hz, 2 H, CH2CH3) ppm. 13C NMR: δ = 12.7 (q, CH3C-5),
14.0 (q, CH3CH2), 53.2 (q, OCH3), 61.3 (t, CH3CH2), 108.7 (s, C-
4), 155.4 (s, C-3), 160.4 (s, CO2Me), 160.5 (s, CO2Et), 175.2 (s, C-
5) ppm. MS (EI): m/z (%) = 213 (2) [M]+, 198 (1) [M – Me]+, 182
(2) [M – OMe]+, 168 (8), 167 (8), 82 (22), 59 (75) [CO2Me]+, 43
6.8 Hz,
2 H, CO2CH2CH3), 4.42 (q, J = 6.8 Hz, 2 H,
CO2CH2CH3), 4.47 (q, J = 7.2 Hz, 2 H, CO2CH2CH3) ppm. 13C
NMR: δ = 13.8 (q, CH3), 13.9 (q, CH3), 63.1 (t, 2 C, 2 COCH2),
106.7 (s, C-3), 148.3 (s, C-4), 155.1 (s, CO2Et), 156.6 (s,
CO2Et) ppm. MS (EI): m/z (%) = 231 (9) [M + 1]+, 230 (4) [M]+,
200 (9), 185 (73), 169 (20), 168 (18), 159 (19), 158 (100), 157 (28),
(100). IR (CDCl ): ν = 2957, 1750 (C=O), 1723 (C=O), 1607,
˜
3
1457 cm–1. C9H11NO5 (213.19): calcd. C 50.70, H 5.20, N 6.57;
found C 50.84, H 4.98, N 6.32.
Ethyl 3-Benzoyl-5-methylisoxazole-4-carboxylate (7d): Treatment of
4 (55 mg) with 1d (175 mg) according to the general procedure gave
7d (11 mg, 10%) as a colourless oil after 72 h (toluene) and chro-
matographic purification (elution with hexane/diethyl ether/trieth-
ylamine, 15:1:1; Rf = 0.21). The same reaction carried out as above,
but with added pyrrolidine (15 mg, 0.214 mmol) gave 7d as a yel-
lowish oil (28 mg, 25%). 1H NMR: δ = 1.00 (t, J = 7.2 Hz, 3 H,
CH2CH3), 2.75 (s, 3 H, CH3C-5), 4.09 (q, J = 7.2 Hz, 2 H,
CH2CH3), 7.45–7.50 (m, 2 H, Ph-Hmeta), 7.59–7.64 (m, 1 H, Ph-
Hpara), 7.87–7.92 (m, 2 H, Ph-Hortho) ppm. 13C NMR: δ = 12.8 (q,
CH3C-5), 13.6 (q, CH3CH2), 61.1 (t, CH3CH2), 109.2 (s, C-4),
128.7 (d, 2 C, Ph-Cmeta), 129.8 (d, 2 C, Ph-Cortho), 134.4 (d, Ph-
Cpara), 135.7 (s, Ph-Cipso), 160.4 (s, CO2Et or C-3), 160.6 (s, CO2Et
or C-3), 175.2 (s, C-5), 186.8 (s, PhCO) ppm. GC–MS (CI): m/z
(%) = 260 (Ͻ1) [M + H]+, 105 (100) [PhCO]+, 77 (19) [Ph]+, 51
141 (25), 130 (96), 111 (18), 100 (32). IR (film): ν = 2987, 1748
˜
(C=O), 1626, 1480, 1374, 1333, 1246 cm–1.
Dimethyl 1,2,5-Oxadiazole-3,4-dicarboxylate 2-Oxide (8b): Methyl
nitroacetate (1b; 126 mg, 1.062 mmol) was added to a mixture of
copper(II) acetate (3.9 mg, 0.0212 mmol) and 1-methylpiperidine
(8.4 mg, 0.0849 mmol) in chloroform (1.4 mL) and the mixture was
magnetically stirred in a sealed vessel at 60 °C. After 96 h the reac-
tion mixture was concentrated and the residue purified by
chromatography on silica gel with hexane/ethyl acetate (8:1; Rf =
0.19) to afford the furoxan 8b as a colourless oil (73 mg, 68%). 1H
NMR: δ = 3.97 (s, 3 H, CO2CH3), 4.02 (s, 3 H, CO2CH3) ppm. 13
C
NMR: δ = 53.9 (q, 2 C, 2 CO2CH3), 106.6 (s, C-3), 148.0 (s, C-4),
155.0 (s, CO2Me), 157.0 (s, CO2Me) ppm. MS (EI): m/z (%) = 202
(1) [M]+, 172 (8), 171 (6) [M – OMe]+, 128 (11), 111 (12), 100 (6),
(14). IR (CDCl ): ν = 3068, 2964, 1724 (C=O), 1682, 1449 (C=O),
˜
3
1599 cm–1. C14H13NO4 (259.26): calcd. C 64.86, H 5.05, N 5.40;
98 (12), 59 (100) [CO Me]+. IR (film): ν = 2958, 1752 (C=O), 1628,
˜
2
1483, 1342, 1312, 1252 cm–1.
found C 65.12, H 5.38, N 5.48.
(4-Nitro-5-phenylisoxazol-3-yl)phenylmethanone (9): Copper(II)
acetate (7.8 mg, 0.0414 mmol) was added to a mixture of benzoyl-
Crystallisation and X-ray Structural Analysis of Compound 9: A
suitable crystal of isoxazole 9 (colourless needle) for X-ray diffrac-
nitromethane (1d; 175 mg, 1.06 mmol) and DABCO (9.6 mg, tion analysis was obtained by recrystallisation from methanol/di-
0.0848 mmol) in chloroform or toluene (1.4 mL) and the mixture
was magnetically stirred in a sealed vessel at 60 °C. After 18 h the
reaction mixture was concentrated and the residue was purified by
chromatography on silica gel, eluting first with hexane/diethyl
ether/triethylamine (15:1:1) to afford benzoylnitromethane (1d; Rf
ethyl ether (3:1). X-ray analysis was carried out with a Siemens P4
diffractometer at room temperature using graphite-monochro-
mated Mo-Kα radiation. The integrated intensities, measured by
using the ω scan mode, were corrected for Lorentzian and polarisa-
tion effects.[41] The structure was solved by direct methods using
= 0.50, 16 mg, 0.097 mmol) and 9 (Rf = 0.21, 46 mg, 29%) and then SIR97[42] and refined by using the full-matrix least-squares on F2
5976
www.eurjoc.org
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 5971–5978

Catalysed Condensation of Activated Nitro Compounds
provided by SHELXL97.[43] The non-hydrogen atoms were refined
anisotropically whereas hydrogen atoms were assigned to calculated
positions and refined isotropically.
Suzuki, Synlett 2003, 1746–1748; c) J. W. Bode, Y. Hachisu, T.
Matsuura, K. Suzuki, Tetrahedron Lett. 2003, 44, 3555–3558;
d) K. B. Umesha, K. Ajay Kumar, K. M. Lokanatha Rai,
Synth. Commun. 2002, 32, 1841–1846.
For recent applications, see: a) Y. Koyama, R. Yamaguchi, K.
Suzuki, Angew. Chem. Int. Ed. 2008, 47, 1084–1087; b) Y.
Hachisu, J. W. Bode, K. Suzuki, J. Am. Chem. Soc. 2003, 125,
8432–8433; c) J. W. Bode, K. Suzuki, Tetrahedron Lett. 2003,
44, 3559–3563.
T. Mukaiyama, T. Hoshino, J. Am. Chem. Soc. 1960, 82, 5339–
5342.
a) E. Kaji, K. Harada, S. Zen, Chem. Pharm. Bull. 1978, 26,
3254–3256; b) K. Harada, E. Kaji, S. Zen, Chem. Pharm. Bull.
1980, 28, 3296–3303.
A. Mckillop, R. J. Kobylecki, Tetrahedron 1974, 30, 1365–1371.
a) G. B. Bachman, L. E. Strom, J. Org. Chem. 1963, 28, 1150–
1152; b) J. E. McMurry, Org. Synth. 1973, 53, 59–62.
For exhaustive literature regarding this synthetic protocol, see
refs. 3–17 in ref.[25] of this paper.
For reactions of aryl isocyanates with compounds containing
active methylene groups in the presence of an organic base,
see, for example: a) O. A. Linchenko, P. V. Petrovskii, I. Yu.
Krasnova, V. N. Kalinin, Z. A. Starikova, Yu. G. Gololobov,
Russ. Chem. Bull. Int. Ed. 2006, 55, 873–878 (Izv. Akad. Nauk.
Ser. Khim. 2006, 844–849); b) Yu. G. Gololobov, O. A. Linch-
enko, I. R. Gol’ding, M. A. Galkina, I. Yu. Krasnova, I. A.
Garbuzova, P. V. Petrovskii, Russ. Chem. Bull. Int. Ed. 2005,
54, 2398–2405 (Izv. Akad. Nauk, Ser. Khim. 2005, 2323–2330);
c) L. Capuano, P. Boschat, H. W. Heyer, G. Wachter, Chem.
Ber. 1973, 106, 312–316; d) L. Capuano, R. Zander, Chem. Ber.
1973, 106, 3670–3673.
For reactions of acyl chlorides with compounds containing
active methylene groups in the presence of an organic base, see,
for example: a) A. A. Akhrem, F. A. Lahkvich, S. I. Budai,
T. S. Khlebnicova, I. I. Petrusevich, Synthesis 1978, 925–927;
b) J.-M. Wang, T. Asami, F.-S. Che, N. Murofushi, S. Yoshida,
J. Agric. Food Chem. 1997, 45, 2728–2734.
For reactions of anhydrides with compounds containing active
methylene groups in the presence of an organic base, see, for
example: H.-G. Henning, G. Mazunaitis, Monatsh. Chem.
1992, 123, 93–98.
C16H10N2O4, M = 294.26, monoclinic, space group P21/n, a =
5.7370(10), b = 12.1950(10), c = 19.844(3) Å, β = 95.940(10)°, V =
1380.9(3) Å3, Z = 4, Dc = 1.415, µ = 0.104 mm–1, F(000) = 608.
12191 reflections were collected in a 1.96ՅθՅ25.0 range; 2414
were independent, the number of parameters was 239 and the final
R index 0.0399 for reflections having IՆ2σI.
[7]
[8]
[9]
CCDC-721723 contains the supplementary crystallographic data
for this paper. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
[10]
[11]
Supporting Information (see also the footnote on the first page of
this article): 1H and 13C NMR data for isoxazoles 5–7, a plot of
concentration versus time for the reaction between 1d and 2, 1H
and gHMBC NMR spectra for compounds 6b and 9.
[12]
[13]
Acknowledgments
The authors thank Università di Firenze for financial support and
the Centro di Analisi e Determinazioni Strutturali of the Università
di Siena for X-ray data collection. E. T. thanks Ente Cassa di Ris-
parmio di Firenze for a doctoral fellowship. Financial support from
the Ente Cassa di Risparmio di Firenze for the purchase of the
400 NMR spectrometer is gratefully acknowledged. Mrs Brunella
Innocenti and Mr Maurizio Passaponti (Università di Firenze) are
acknowledged for technical support. Dr C. Faggi is acknowledged
for her assistance on crystallographic data elaboration.
[14]
[15]
[1] D. Giomi, F. M. Cordero, F. Machetti, in: Comprehensive Het-
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Scriven, R. Taylor), Elsevier, 2008, p. 430.
[2] a) A. Quilico, R. Fusco, Rend. Ist. Lomb. 1936, 69, 439–457;
b) A. Quilico, R. Fusco, Gazz. Chim. Ital. 1937, 67, 589–603;
c) R. Fusco, Rend. Ist. Lomb. 1937, 70, 225–235; d) L. Panizzi,
Gazz. Chim. Ital. 1939, 69, 322–329; e) L. Panizzi, Gazz. Chim.
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