Isoxazoles and isoxazolines by 1,3-dipolar cycloaddition: Base-catalysed condensation of primary nitro compounds with dipolarophiles

Article abstract of DOI:10.1002/ejoc.200700276

1,4-Diazabicyclo[2.2.2]octane (DABCO) or other suitable N-bases cause primary activated nitro compounds to condense with alkenes to yield isoxazolines or with alkynes to give isoxazoles. As the molar ratio of the base with respect to the dipolarophile dec

Full text of DOI:10.1002/ejoc.200700276

FULL PAPER
DOI: 10.1002/ejoc.200700276
Isoxazoles and Isoxazolines by 1,3-Dipolar Cycloaddition: Base-Catalysed
Condensation of Primary Nitro Compounds with Dipolarophiles
Fabrizio Machetti,*[a] Luca Cecchi,[b] Elena Trogu,[b] and Francesco De Sarlo*[b]
Keywords: Nitro compounds / Cycloaddition / Condensation / Catalysis / Nitrogen heterocycles
1,4-Diazabicyclo[2.2.2]octane (DABCO) or other suitable N-
bases cause primary activated nitro compounds to condense
with alkenes to yield isoxazolines or with alkynes to give
isoxazoles. As the molar ratio of the base with respect to the
dipolarophile decreased, the reaction became slower, but the
nitro compound became more resistant to hydrolytic cleav-
age. The best results were achieved with a molar ratio of
base in the range of 0.05–0.1. The reactions were carried out
in chloroform at 60 °C; for ethyl nitroacetate and phenylni-
tromethane, ethanol at 80 °C can be employed with better
results and shorter reaction times. A catalytic cycle is pro-
posed: in chloroform the hydrogen-bonded ion pair formed
between the nitronate and the protonated base undergoes
reversible cycloaddition with the dipolarophile and then the
hydrogen-bonded intermediate adduct releases water by re-
action with a second nitro molecule to give the product and
the hydrogen-bonded nitronate.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2007)
polarophile) and solvents would allow the reaction to occur.
We recently reported[6–8] that the dehydration of “acti-
vated” primary nitro compounds, including phenylnitro-
methane, is achieved with 1,4-diazabicyclo[2.2.2]octane
(DABCO) or other bases provided dipolarophiles are pres-
ent, thus leading directly to the expected cycloadducts. No
dehydrating agents are required: the reaction proceeds even
in the presence of water. A major drawback of water, com-
bined with the presence of a base, concerns the facile de-
composition of the activated nitro compounds (1a–e).
The mechanism we have proposed for the reaction im-
plies that the base behaves as a catalyst. Therefore we con-
sider here how the reaction is affected when the amount of
base is lowered to catalytic quantities.[9,10]
Introduction
The importance of isoxazole derivatives has stimulated
the development of many methods for their synthesis,[1,2]
including the use of primary nitro compounds as precursors
of 1,3-dipoles, affording isoxazoles and isoxazolines by 1,3-
dipolar cycloaddition (1,3-DC).[3] By this retrosynthetic ap-
proach, alkyl-, acyl- or silylnitronates or nitrile oxides can
be used as 1,3-dipoles depending on the reagents employed.
Acidic dehydrating agents[4] have been utilised at high
temperatures, while acylating or alkylating reagents have
been utilised with a base.[5] These methods have in general
an unfavourable environmental impact and in addition suf-
fer from drawbacks arising from the dipole (dimerisation or
polymerisation) or the dehydrating agent (byproducts) and
limitations derived from interference by other functional
groups present in the reagents. Consequently, product isola-
tion and purification is often complicated by these contami-
nants and yields may be low.
Results and Discussion
The title reactions are illustrated in Scheme 1: di-
polarophiles bearing functional groups such as OH or NO2
have been included with the aim of illustrating the substrate
scope of the method.
Considering that the loss of water is irreversible in the
above processes, a dehydrating reagent appears not to be an
essential component of the reaction. Thus, we investigated
which kinds of reagents (nitro compound, base and di-
[a] 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
[b] 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
Scheme 1. Synthetic approach and nitro compounds/dipolarophiles
used in this study.
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Isoxazoles and Isoxazolines by 1,3-Dipolar Cycloaddition
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Figure 1. Condensation of nitro compounds with dipolarophiles catalysed by organic bases. Effect of the base/dipolarophile ratio on the
conversion of the dipolarophile into the cycloadduct and on the decomposition of the nitro compound (1a–1d, 1f in chloroform, 1e in
ethanol). The molar ratios of the product (solid squares) and of the residual nitro compound (white triangles) (with respect to the
dipolarophile and detected by 1H NMR spectroscopy after the established time) are reported as a function of the molar ratio of the base.
Nitro compound (0.75 m) + dipolarophile (0.30 m) at 60 °C: (A)–(D) and (F) in chloroform, (E) in ethanol. (A) NMI, 20 h; B) DABCO,
40 h; C) DABCO, 20 h; D) DABCO, 40 h; E) DABCO, 40 h; F) 4-DMAP, 40 h.
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Several reactions were chosen as models for this study compounds (1a, 1b and 1c): in fact, the total amount (resid-
(Figure 1A–F). These were carried out under the usual con- ual + converted into adduct) detected at the end is largely
ditions: nitro compound 1 + dipolarophile + base (molar below the amount engaged in the reaction (2.5 molar frac-
ratios: 2.5:1:variable, ranging from 0.025 to 1) at 60 °C in tion with respect to the dipolarophile). However, as the
chloroform except for one example carried out in ethanol amount of base is lowered, the decomposition of the nitro
(5b, Figure 1E). The base employed was N-methylimidazole compounds is less severe: some minor variations depend on
(NMI) for the reaction leading to the adduct 7a in order to which base, nitro compound or solvent is involved. The
avoid a side-reaction leading to furazan derivatives from the conversion into products observed after the established time
reagents benzoylnitromethane (1a) and the dipolarophile in results from a balance between the reaction rate (increasing
the molar ratio 2:1.[7] In the other reactions (Figure 1B–D), with the molar ratio of the base) and the stability of the
DABCO was used as the base. For comparison, the reaction starting nitro compound (decreasing as the molar ratio of
leading to 5b was also studied with 4-(dimethylamino)pyr- the base increases). When the conversion is incomplete, a
idine (4-DMAP) as the base (Figure 1F).
longer reaction time might ensure an increased yield only if
After the time indicated, the reacting mixtures were ana- some nitro compound is still present (e.g., 6c, at a molar
1
lysed by H NMR spectroscopy and the molar ratios be- ratio of 0.1 DABCO, Figure 1C): the excess of the nitro
tween the product, nitro compound and dipolarophile compound (2.5 times the dipolarophile) we employed in our
evaluated relative to the dipolarophile (residual + amount experiments was aimed at enhancing the conversion of the
converted into adduct). For each molar ratio of base (with dipolarophile into the product. The use of ethanol as the
respect to the dipolarophile employed) we report (Fig- solvent gave good results with ethyl nitroacetate (1a) and
ure 1A–F) the molar ratios of the dipolarophile converted phenylnitromethane (1e), whereas the other nitro com-
into the product (solid squares) and the residual nitro com- pounds were more rapidly cleaved in this solvent.
pound (white triangles).
The reaction conditions were selected on the basis of the
The presence of the base (with the water produced in the above results and the compounds prepared are reported in
reaction) causes considerable decomposition[11] of the nitro Table 1. Compared with previous results (when available)
Table 1. Base-catalysed synthesis of isoxazolines and isoxazoles by condensation of primary nitro compounds and dipolarophiles.[a]
1
[a] See the Experimental Section for details. [b] Relative to the dipolarophile. [c] Conversion of dipolarophiles, determined by H NMR
spectroscopy. [d] Isolated yield, determined on the analytically pure product and based on the dipolarophile. [e] Not determined: signals
1
are not well resolved in the H NMR spectra. [f] Obtained with 5 equiv. of ethyl nitroacetate instead of 2.5 equiv. and in a longer time
of 90 h.
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Isoxazoles and Isoxazolines by 1,3-Dipolar Cycloaddition
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the yields are higher [products 2b (83%),[12] 7a (34%),[13] 8b
(61%),[14] 5e (54%)[15] and 5b (70%)[16]] or similar [products
2e (98%)[17] and 7c (85%)[18]].
All the reactions were carried out in chloroform except
for that of 2-butyne-1,4-diol which was carried out in etha-
nol (Entries 20 and 21) because of the low solubility of this
dipolarophile in chloroform. From dipolarophiles contain-
ing monosubstituted multiple bonds, only the 5-substituted
regioisomers were detected by 1H NMR spectroscopy.
However, in the reaction of ethyl nitroacetate (1b) with allyl
alcohol, carried out on a larger scale, besides the 5-hy-
droxymethyl regioisomer 3b, a minor amount of the 4-hy-
droxymethyl regioisomer 4b was detected and isolated by
repeated chromatography.
For the reactions of benzoylnitromethane (1a, Entries 10
and 13), N-methylimidazole (NMI) was employed for the
above-mentioned reason, with excellent results.
Scheme 2. Plausible mechanism for the catalysed condensation of
nitro compounds and dipolarophiles.
The reactions of benzoylnitromethane (1a) and of nitro-
acetamides (1c and 1d) could not be carried out in ethanol
as cleavage is easier than in chloroform. However, reactions
of ethyl nitroacetate (1b), leading to 3b, 5b, 8b and 9b (En-
tries 4, 7, 19 and 20), and of phenylnitromethane (1e), lead-
ing to 5e (Entry 9), could be profitably performed in etha-
nol (Figure 1E): the reaction temperature can be raised to
80 °C with considerable reduction of reaction time and en-
hancement of conversion (Entries 4, 9 and 19). The pres-
ence of a hydroxy group in the dipolarophile does not inter-
fere with the reaction (100% conversion observed: En-
tries 4, 7, 9 and 19). The reduced yield of 8b observed in
CHCl3, in spite of a quantitative conversion (Entry 17), is
ascribed to partial intermolecular transesterification: the
product is protected when ethanol is the solvent (Entry 19).
The catalytic use of 4-(dimethylamino)pyridine (see Fig-
ure 1F), applied in two cases (Table 1, Entries 6 and 21),
gave the same results as those obtained with DABCO, but
required a lower concentration of the base (Entry 5 vs. En-
try 6), while for the sluggish reaction with 2-butyne-1,4-diol
no improvement was observed (Entry 21).
The illustrated catalytic cycle, relevant to a solvent of low
polarity such as chloroform, rests upon the following evi-
dence. (i) nitro compounds 1a–e, having pKHB Յ 7, on mix-
ing with DABCO react to give ammonium salts either as
separate ions or as hydrogen-bonded complexes depending
on the solvent polarity; (ii) these nitro compounds are unaf-
fected by dipolarophiles in the absence of a base or other
reagents; (iii) from nitro compounds and a catalytic amount
of base, isoxazoles are produced from alkynes and 4,5-dihy-
droisoxazoles from alkenes; (iv) changing the base has
shown that its efficiency is related to the stability of the
hydrogen bond between the nitronate and the protonated
base. Indeed, in other solvents the reaction is not favoured
when ion separation is caused by highly polar solvents
(DMSO, acetonitrile) unless a hydroxy group (ethanol) en-
sures hydrogen-bonding to the anion.[8]
Experimental Section
General: Melting points were recorded with a Büchi 510 apparatus
and are uncorrected. Chromatographic separations 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 carried out on
25-mm silica gel plates (Merck F254) with the eluent indicated for
the column chromatography. For gradient column chromatography
Rf values refer to the more polar eluent. 1H and 13C NMR spectra
were recorded with a Mercuryplus 400 spectrometer (operating at
400 MHz for 1H and 100.58 MHz for 13C). The multiplicities of
the 13C NMR signals and assignments were determined by means
The preparation of 3b from ethyl nitroacetate (1b) and
allyl alcohol in ethanol was repeated on a larger scale
(0.349 g of dipolarophile converted) with no significant dif-
ference to the result reported in Table 1 (Entry 4), but the
minor regioisomer 4b was identified.
Conclusions
The illustrated examples unequivocally show that pri- of HMQC and gHMBC experiments. Chemical shifts were deter-
mined relative to the residual solvent peak (CHCl3: δ = 7.24 ppm
for 1H NMR and δ = 77.0 ppm for 13C NMR). EI (electron impact)
mass spectra (at an ionising voltage of 70 eV) were obtained using
a Shimadzu QP5050A quadrupole-based mass spectrometer. Ion
mass/charge ratios (m/z) are reported in atomic mass units followed
by the intensities relative to the base peak in parentheses. IR spec-
tra were recorded with a Perkin-Elmer 881 spectrometer. Elemental
analyses were obtained with an Elemental Analyser Perkin-Elmer
240C apparatus. Phenylnitromethane and N-methyl-2-nitroacet-
amide were prepared according to reported procedures.[8] Commer-
cially available (Lancaster and Aldrich) benzoylnitromethane and
mary activated nitro compounds condense with di-
polarophiles to form isoxazole derivatives under organic ca-
talysis by DABCO or other suitable N-bases. An attempted
rationalisation of the mechanism is depicted in Scheme 2:
in chloroform the hydrogen-bonded ion pair formed be-
tween the nitronate and the protonated base undergoes re-
versible cycloaddition with the dipolarophile and then the
hydrogen-bonded intermediate adduct releases water by re-
action with a second nitro molecule to give the product and
the hydrogen-bonded nitronate.
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F. Machetti, L. Cecchi, E. Trogu, F. De Sarlo
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ethyl nitroacetate, were used as supplied. DABCO, 4-DMAP and
NMI are commercially available and used as supplied. CHCl3 (eth-
anol-free) was filtered through a short pad of potassium carbonate
just before use. Allyl alcohol and propargyl alcohol were distilled
before use. 2-Butyne-1,4-diol was crystallised (AcOEt) before use.
using DABCO (0.1 equiv.) as the base. The residue was dissolved
in diethyl ether (15 mL), washed with brine (3ϫ15 mL portions),
satd. Na2CO3 solution (3ϫ15 mL portions), and brine again
(3ϫ15 mL portions). The organic layer was dried (sodium sulfate),
filtered and concentrated. Clear oil. Yield: 89 mg, 100%.
C11H15NO3 (209.2): calcd. C 63.14, H 7.23, N 6.69; found C 63.36,
H 7.52, N 6.40. The spectral data are identical to those previously
reported.[8]
Isoxazoline 2e (5-Phenyl-3-oxa-4-azatricyclo[5.2.1.02,6]dec-4-ene):
Isoxazoline 2e was prepared according to the general procedure
from 1e and norbornene in chloroform at 60 °C (72 h) using
DABCO (0.1 equiv.) as the base. The residue was dissolved in di-
ethyl ether (15 mL), washed with water (3ϫ15 mL portions), 1 m
NaOH (3ϫ15 mL portions) and brine (3ϫ15 mL portions) in se-
quence. The organic layer was dried (sodium sulfate), filtered and
concentrated. The crude product was triturated in ice-cold diethyl
ether and then filtered. Yellowish solid. Yield: 89 mg, 98%. M.p.
95–97 °C (ref.[8] 98–99 °C). C14H15NO (213.28): calcd. C 78.84, H
7.09, N 6.57; found C 78.87, H 7.09, N 6.42. The spectral data are
identical to those previously reported.
Effect of the Amount of Base on the Conversion of the Dipolarophile
(Figure 1A–F): Different amounts of base were screened in an ap-
paratus in which 6–8 reactions were carried out simultaneously. The
base (DABCO, NMI or 4-DMAP), in a variable base/dipolarophile
molar ratio (1, 0.75, 0.5, 0.25, 0.175, 0.10, 0.05, 0.025), dipolaro-
phile (0.424 mmol), nitro compound (1.06 mmol) and solvent
(chloroform or ethanol, 1.4 mL) were stirred at 60 °C in a sealed
tube for the indicated time. For the 0.025 base/dipolarophile molar
ratio, twice the amount of reagents and solvent was used. After the
requested time, an aliquot portion was withdrawn and diluted with
CDCl3 (0.6 mL). After addition of TFA (4ϫ10–3 mL), the 1H
NMR spectrum was recorded and the conversion (as a molar ratio)
was evaluated as follows. Benzoylnitromethane and phenylacetyl-
ene (Figure 1A): by integrating the 4-H proton signal of the cy-
cloadduct 7a [δ = 7.03 (s) ppm] and the acetylenic proton of phenyl-
acetylene [δ = 3.05 (s) ppm]. Ethyl nitroacetate and norbornene
(Figure 1B): by integrating the CHON proton signal [δ = 4.64 (d)
ppm] of the cycloadduct 2b and the ethylene protons of norbornene
[δ = 5.98 (s) ppm]. N-Methyl-2-nitroacetamide and 5-nitro-1-pen-
tene (Figure 1C): by integrating the 5-H proton signal [δ = 4.70–
4.80 (m) ppm] of the cycloadduct 6c and an ethylene proton of 5-
nitro-1-pentene [δ = 5.64–5.88 (m) ppm]. Ethyl nitroacetate and 3-
buten-1-ol (Figure 1D): by integrating the 5-H proton signal [δ =
4.78–5.08 (m) ppm] of the cycloadduct 5b and an ethylene proton
of 3-buten-1-ol [δ = 5.68–5.88 (m) ppm]. The residual nitro com-
pound was evaluated by integrating its methylene protons (δ = 5.88,
5.19, 5.08 ppm for 1a, 1b and 1c, respectively). Without base no
conversion was observed. In the case of an unclear result a dupli-
cate experiment was run.
Isoxazoline 3b [Ethyl 5-(Hydroxymethyl)-4,5-dihydro-3-isoxazole-
carboxylate]: Isoxazoline 3b was prepared according to the general
procedure from 1b and allyl alcohol in ethanol at 80 °C (36 h) using
DABCO (0.10 equiv.) as the base. The residue was dissolved in
dichloromethane (10 mL), silica gel (200 mg) was added to the mix-
ture and the solvent evaporated. The silica gel with the adsorbed
product was loaded onto the top of a column of silica gel and
purified by chromatography. Eluent: hexane/diethyl ether, 6:1, then
diethyl ether, Rf = 0.31. Clear liquid. Yield: 70 mg, 95%. 1H NMR:
δ = 1.34 (t, J = 7.2 Hz, 3 H, CH3CH2O), 1.96 (br. s, 1 H, OH),
3.05–3.28 (m, 2 H, 4-H), 3.62 (dd, J = 4.4 and 12.4 Hz, 1 H,
CHOH), 3.84 (dd, J = 3.2 and 12.4 Hz, 1 H, CHOH), 4.33 (q, J =
7.2 Hz, 2 H, CH3CH2O), 4.84–4.93 (m, 1 H, 5-H) ppm. 13C NMR:
δ = 14.1 (q, CH3CH2O), 34.8 (t, C-4), 62.1 (t, CH3CH2O), 63.3 (t,
CH2OH), 83.8 (d, C-5), 152.1 (s, C-3), 160.4 (s, C=O) ppm. IR
Preparation of N-Benzyl-2-nitroacetamide (1d): A mixture of ethyl
nitroacetate (1b) (1.33 g, 10 mmol) and benzylamine (10.9 mL,
10 equiv.) was heated whilst stirring at 60 °C. After 16 h, the mix-
ture was cooled and 3 n HCl was added to pH = 3. The mixture
was then extracted with diethyl ether (2ϫ30 mL). The combined
organic layers were washed with 5% HCl (2ϫ15 mL), dried with
Na2SO4, filtered and concentrated in vacuo. Trituration of the re-
sultant solid with cold Et2O afforded the amide 1d as a white solid.
Yield: 0.970 g, 50%. M.p. 97–98 °C (ref.[19] 87–89 °C). 1H NMR: δ
= 4.48 (d, J = 5.6 Hz, 2 H, CH2Ph), 5.08 (s, 2 H, CH2NO2), 6.77
(br. s, 1 H, NH), 7.26–7.38 (m, 5 H, Ph-H) ppm. 13C NMR: δ =
44.1 (t, CH2Ph), 77.7 (t, CH2NO2), 127.8 (d, 2 C, Ph-C), 128.1 (d,
Ph-C), 128.9 (d, 2 C, Ph-C), 136.6 (s, Ph-C), 159.8 (s, C=O) ppm.
(CDCl ): ν = 3600 (OH), 2985, 1720 (C=O), 1593 (C=N),
˜
3
1258 cm–1. MS (EI): m/z (%) = 173 (4) [M]+, 142 (39), 128 (27), 70
(100). C7H11NO4 (173.17): calcd. C 48.55, H 6.40, N 8.09; found
C 48.26, H 6.39, N 7.88.
Isoxazoline 5b [Ethyl 5-(2-Hydroxyethyl)-4,5-dihydro-3-isoxazole-
carboxylate]: Isoxazoline 5b was prepared according to the general
procedure from 1b (4.24 mmol) and 3-buten-1-ol in chloroform at
60 °C (40 h) using DABCO (0.175 equiv.) as the base. The residue
was purified by chromatography to afford 310 mg (97%) of 5b. In
other experiments carried out according to the general procedure
the reaction carried out in chloroform at 60 °C using 4-DMAP
(0.1 equiv.) as the base or in ethanol at 80 °C using DABCO
(0.175 equiv.) as the base afforded the isoxazoline 5b in 96 and 97%
yields, respectively. Eluent: dichloromethane then dichloromethane/
methanol, 20:1, Rf = 0.27. Clear oil. 1H NMR: δ = 1.32 (t, J =
7.1 Hz, 3 H, CH3CH2O), 1.81–1.87 (m, 1 H, CH2C-5), 1.91–1.99
(m, 1 H, CH2C-5), 2.04 (br. s, 1 H, OH), 2.89 (dd, J = 8.0 and
18.0 Hz, 1 H, 4-H), 3.28 (dd, J = 11.2 and 18.0 Hz, 1 H, 4-H),
3.72–3.82 (m, 2 H, CH2OH), 4.29 (q, J = 7.1 Hz, 2 H, CH3CH2O),
4.90–5.00 (m, 1 H, 5-H) ppm. 13C NMR: δ = 14.2 (q, CH3CH2O),
37.7 (t, CH2C-5), 38.9 (t, C-4), 59.1 (t, CH2OH), 62.1 (t,
CH3CH2O), 81.7 (d, C-5), 151.5 (s, C-3), 160.5 (s, C=O) ppm. IR
IR (CDCl ): ν = 3419 (NH), 1692 (C=O), 1564, 1527 cm–1. MS
˜
3
(EI): m/z (%) = 194 (1) [M]+, 148 (100) [M – NO2]+, 133 (6)
[PhCH2NCO]+, 107 (81), 91 (89) [PhCH2]+. C9H10N2O3 (194.19):
calcd. C 55.67, H 5.19, N 14.43; found C 55.85, H 5.10, N 14.28.
General Procedure for the Preparation of Isoxazolines 1–6 and Isox-
azoles 7–9: A solution of nitro compound (1a–e) (1.06 mmol unless
otherwise stated, 2.5 equiv.), base (0.05–0.175 equiv.) and di-
polarophile (0.424 mmol, 1 equiv.) in chloroform or ethanol
(1.4 mL) was stirred for the indicated time in a sealed vessel
(Schlenk) at 60 or 80 °C. The solvent was then removed and the
residue purified by chromatography directly or after the reported
workup.
(CDCl ): ν = 3625 (OH), 1720 (C=O), 1589 (C=N), 1381,
˜
3
1257 cm–1. MS (EI): m/z (%) = 187 (1) [M]+, 142 (100) [M –
OEt]+, 114 (66) [M – CO2Et]+, 96 (28). C8H13NO4 (187.19): calcd.
C 51.33, H 7.00, N 7.48; found C 51.65, H 6.97, N 7.70.
Isoxazoline 2b (Ethyl 3-Oxa-4-azatricyclo[5.2.1.02,6]dec-4-ene-5-
carboxylate): Isoxazoline 2b was prepared according to the general
procedure from 1b and norbornene in chloroform at 60 °C (40 h)
Isoxazoline 5e [(3-Phenyl-4,5-dihydroisoxazol-5-yl)ethanol]: Isox-
azoline 5e was prepared according to the general procedure from
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Isoxazoles and Isoxazolines by 1,3-Dipolar Cycloaddition
FULL PAPER
1e and 3-buten-1-ol in ethanol at 80 °C (40 h) using DABCO
(0.10 equiv.) as the base. The residue was purified by chromatog-
raphy to afford 76 mg (94%) of 5e. In another experiment carried
out according to the general procedure, the reaction in chloroform
at 60 °C (40 h) using DABCO (0.10 equiv.) as the base afforded the
isoxazoline 5e in 49% yield. Eluent: hexane then hexane/ethyl ace-
procedure from 1c and 5-nitro-1-pentene in chloroform at 60 °C
(120 h) using DABCO (0.05 equiv.) as the base. The residue was
dissolved in ethyl acetate (15 mL) and washed with brine
(3ϫ15 mL portions), 1 m NaOH (3ϫ15 mL portions), and brine
again (3ϫ15 mL portions). The organic layer was dried (sodium
sulfate), filtered and concentrated to afford 6c (70 mg). More 6c
was obtained by back-extraction of the combined aqueous layers
1
tate, 2:3, Rf = 0.28. White solid. M.p. 78–79 °C (ref.[20] 78 °C). H
NMR: δ = 1.86–1.95 (m, 1 H, CH2C-5), 1.96–2.05 (m, 1 H, CH2C- with ethyl acetate (3ϫ30 mL) and concentration of the extracts
5), 3.06 (dd, J = 8.0 and 16.4 Hz, 1 H, 4-H), 3.46 (dd, J = 10.4 and (10 mg). White solid. Yield: 80 mg, 88%. M.p. 75–76 °C. 1H NMR:
16.4 Hz, 1 H, 4-H), 3.82–3.92 (m, 2 H, CH2OH), 4.88–4.96 (m, 1
H, 5-H), 7.36–7.42 (m, 3 H, Ph-H), 7.62–7.68 (m, 2 H, Ph-H) ppm.
δ = 1.62–1.78 (m, 2 H, CH2C-5), 2.02–2.20 (m, 2 H, CH2CH2C-5),
2.87 (d, J = 5.2 Hz, 3 H, CH3), 2.88 (dd, J = 8.0 and 17.9 Hz, 1
13C NMR: δ = 37.8 (t, CH2C-5), 40.5 (t, C-4), 59.9 (t, CH2OH), H, 4-H), 3.30 (dd, J = 10.9 and 17.9 Hz, 1 H, 4-H), 4.36–4.48 (m,
79.5 (d, C-5), 126.6 (d, 2 C, Ph-C), 128.7 (d, 2 C, Ph-C), 129.5 (s,
2 H, CH2NO2), 4.70–4.80 (m, 1 H, 5-H), 6.64 (br. s, 1 H, NH)
Ph-C), 130.1 (d, Ph-C), 156.8 (s, C-3) ppm. IR (CDCl ): ν = 3623 ppm. 13C NMR: δ = 23.3 (t, CH2CH2C-5), 26.1 (q, CH3N), 31.8
˜
3
(OH), 1601, 1356 cm–1. MS (EI): m/z (%) = 191 (13) [M]+, 146
(t, CH2C-5), 38.6 (t, C-4), 74.9 (t, CH2NO2), 82.3 (d, C-5), 153.9
(100) [M – CH2CH2OH]+, 118 (29), 77 (75) [Ph]+. C11H13NO2 (s, C-3), 160.1 (s, C=O) ppm. IR (CDCl ): ν = 3434 (N-H), 2941,
˜
3
(191.23): calcd. C 69.09, H 6.85, N 7.32; found C 68.80, H 6.55, N
7.15.
1678 (C=O), 1595, 1555 cm–1. MS (EI): m/z (%) = 215 (1) [M]+,
185 (1) [M – NHCH3]+, 58 (100) [CONHMe]+. C8H13N3O4
(215.21): calcd. C 44.65, H 6.09, N 19.53; found C 44.35, H 6.10,
N 19.68.
Isoxazoline 6a {[5-(3-Nitropropyl)-4,5-dihydro-3-isoxazolyl](phenyl)-
methanone}: Isoxazoline 6a was prepared according to the general
procedure from 1a and 5-nitro-1-pentene in chloroform at 60 °C
(72 h) using NMI (0.05 equiv.) as the base. The residue was dis-
solved in diethyl ether (15 mL), washed with brine (3ϫ15 mL por-
tions), 3 m NaOH (3ϫ15 mL portions) and brine again (3ϫ15 mL
portions). The organic layer was dried (sodium sulfate), filtered
and concentrated. The residue was dissolved in dichloromethane
(10 mL), silica gel (200 mg) was added to the mixture and the sol-
vent evaporated. The silica gel with the adsorbed product was
loaded onto the top of a column of silica gel and purified by
chromatography. Eluent: hexane/diethyl ether, 6:1, then hexane/di-
Isoxazole 7a [(Phenyl)(5-phenyl-3-isoxazolyl)methanone]: Isoxazole
7a was prepared according to the general procedure from 1a and
phenylacetylene in chloroform at 60 °C (20 h) using 1-methylimid-
azole (0.05 equiv.) as the base. The solvent was then removed and
the residue dissolved in diethyl ether (15 mL), washed with brine
(3ϫ15 mL portions), 1 m NaOH (3ϫ15 mL portions) and brine
again (3ϫ15 mL portions). The organic layer was dried (sodium
sulfate), filtered and concentrated. When necessary the workup was
repeated. White solid. Yield: 103 mg, 97%. M.p. 77–78 °C (ref.[21]
78–79 °C). C16H11NO2 (249.27): calcd. C 77.10, H 4.45, N 5.62;
found C 77.31, H 4.69, N 6.01. The spectral data are identical to
those previously reported.[7]
1
ethyl ether, 3:2, Rf = 0.15. Clear oil. Yield: 93 mg, 83%. H NMR:
δ = 1.73–1.88 (m, 2 H, CH2C-5), 2.10–2.30 (m, 2 H, CH2CH2C-5),
3.02 (dd, J = 8.0 and 17.8 Hz, 1 H, 4-H), 3.43 (dd, J = 10.8 and
17.8 Hz, 1 H, 4-H), 4.39–4.52 (m, 2 H, CH2NO2), 4.77–4.86 (m, 1
H, 5-H), 7.42–7.50 (m, 2 H, Ph-Hmeta), 7.56–7.62 (m, 1 H, Ph-
Hpara), 8.14–8.21 (m, 2 H, Ph-Hortho) ppm. 13C NMR: δ = 23.4 (t,
CH2CH2C-5), 32.0 (t, CH2C-5), 39.2 (t, C-4), 74.9 (t, CH2NO2),
81.9 (d, C-5), 128.2 (d, 2 C, Ph-Cmeta), 130.1 (d, 2 C, Ph-Cortho),
133.5 (d, Ph-Cpara), 135.4 (s, Ph-Cipso) 157.5 (s, C-3), 185.9 (s, C=O)
Isoxazole 7c (N-Methyl-5-phenyl-3-isoxazolecarboxamide): Isox-
azole 7c was prepared according to the general procedure from 1c
and phenylacetylene in chloroform at 60 °C (72 h) using DABCO
(0.05 equiv.) as the base. The residue was dissolved in diethyl ether
(15 mL) and washed with brine (3ϫ15 mL portions), 1 m NaOH
(3ϫ15 mL portions) and brine again (3ϫ15 mL portions) in se-
quence. The organic layer was dried (sodium sulfate), filtered and
concentrated. White solid. Yield: 73 mg, 84%. M.p. 192–193 °C
(ref.[8] 198–199 °C). C11H10N2O2 (202.21): calcd. C 65.34, H 4.98,
N 13.85; found C 64.95, H 5.21, N 13.95. The spectral data are
identical to those previously reported.[7]
ppm. IR (CDCl ): ν = 2936, 1652 (C=O), 1598 (C=N) 1555
˜
3
(ON–O), 1365 (ON–O) cm–1. MS (EI): m/z (%) = 262 (7) [M]+, 174
(42), 105 (100) [PhCO]+, 77 (83) [Ph]+. C13H14N2O4 (262.26): calcd.
C 59.54, H 5.38, N 10.68; found C 59.34, H 4.92, N 10.33.
Isoxazoline 6b [Ethyl 5-(3-Nitropropyl)-4,5-dihydro-3-isoxazole-
carboxylate]: Isoxazoline 6b was prepared according to the general
procedure from 1b and 5-nitro-1-pentene in chloroform at 60 °C
(72 h) using DABCO (0.10 equiv.) as the base. The residue was
purified by chromatography. Eluent: hexane/diethyl ether, 1:1, Rf =
Isoxazole 7d (N-Benzyl-5-phenyl-3-isoxazolecarboxamide): Isox-
azole 7d was prepared according to the general procedure from 1d
and phenylacetylene in chloroform at 60 °C (72 h) using DABCO
(0.05 equiv.) as the base. The residue was dissolved in diethyl ether
(15 mL) and washed with water (3ϫ15 mL portions), 1 m NaOH
(3ϫ15 mL portions) and brine (3ϫ15 mL portions) in sequence.
The organic layer was dried (sodium sulfate), concentrated and the
residue dissolved in dichloromethane (6 mL). Silica gel (200 mg)
was added to the mixture and the solvent evaporated. The silica
gel with the adsorbed product was loaded onto the top of a column
of silica gel and purified by chromatography. Eluent: hexane/diethyl
ether, 3:1, Rf = 0.25. White solid. Yield: 77 mg, 68%. M.p. 151–
152 °C (ref.[22] 152 °C). 1H NMR: δ = 4.64 (d, J = 5.8 Hz, 2 H,
CH2Ph), 6.98 (s, 1 H, 4-H), 7.10–7.19 (br. s, 1 H, NH), 7.27–7.32
(m, 1 H, Bn-H), 7.33–7.36 (m, 4 H, Bn-H), 7.44–7.50 (m, 3 H, Ph-
Hmeta and Ph-Hpara), 7.78–7.80 (m, 2 H, Ph-Hortho) ppm. 13C NMR:
δ = 43.5 (t, NCH2Ph), 99.2 (d, C-4), 125.9 (d, 2 C, Ph-Cortho), 126.8
(s, Ph-Cipso), 127.8 (d, Bn-C), 127.9 (d, 2 C, Bn-C), 128.8 (d, 2 C,
Bn-C), 129.1 (d, 2 C, Ph-Cmeta), 130.7 (d, Ph-Cpara), 137.3 (s, Bn-
1
0.30. Clear liquid. Yield: 96 mg, 98%. H NMR: δ = 1.32 (t, J =
7.0 Hz, 3 H, CH3CH2), 1.68–1.82 (m, 2 H, CH2C-5), 2.04–2.22 (m,
2 H, CH2CH2C-5), 2.83 (dd, J = 8.0 and 17.8 Hz, 1 H, 4-H), 3.29
(dd, J = 10.9 and 17.8 Hz, 1 H, 4-H), 4.30 (q, J = 7.0 Hz, 2 H,
CH3CH2), 4.36–4.48 (m, 2 H, CH2NO2), 4.76–4.84 (m, 1 H, 5-H)
ppm. 13C NMR: δ = 14.0 (q, CH3CH2), 23.1 (t, CH2CH2C-5), 31.8
(t, CH2C-5), 38.6 (t, C-4), 62.1 (t, CH3CH2), 74.8 (t, CH2NO2),
82.5 (d, C-5), 151.4 (s, C-3), 160.4 (s, C=O) ppm. IR (CDCl ): ν =
˜
3
1720 (C=O), 1590 (C=N) 1555 (ON–O), 1379, (ON–O) cm–1. MS
(EI): m/z (%) = 231 (6) [MH]+, 213 (4), 185 (33) [MH – NO2]+,
155 (64), 142 (100) 114 (92) [MH – NO2(CH2)3CHO]+. C9H14N2O5
(230.22): calcd. C 46.95, H 6.13, N 12.17; found C 47.29, H 6.16,
N 12.19.
Isoxazoline 6c [N-Methyl-5-(3-nitropropyl)-4,5-dihydro-3-isoxazole-
carboxamide]: Isoxazoline 6c was prepared according to the general
Eur. J. Org. Chem. 2007, 4352–4359
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4357

F. Machetti, L. Cecchi, E. Trogu, F. De Sarlo
FULL PAPER
Cipso), 158.8 (s, C-3)*, 159.0 (s, C=O)*, 171.7 (s, C-5) ppm; * may
3.86 (m, 2 H, CH2OH), 4.28–4.44 (m, 3 H, CH3CH2O, 5-H), 4.64
(dd, J = 8.8 and 11.2 Hz, 1 H, 5-H) ppm. 13C NMR: δ = 14.0 (q,
CH3CH2O), 49.7 (d, C-4), 62.0 (t, CH2OH), 62.5 (t, CH3CH2O),
be exchanged. IR: ν = 3416 (NH), 1683 (C=O), 1541, 1447 cm–1.
˜
MS (EI): m/z (%) = 278 (37) [M]+, 277 (90) [M – 1]+, 201 (10), 173
(22), 146 (54), 105 (83) [PhCO]+, 91 (100) [PhCH2]+, 77 (60) [Ph]+. 74.6 (t, C-5), 152.1 (s, C-3), 161.6 (s, C=O) ppm. IR (CDCl ): ν =
˜
3
C17H14N2O2 (278.31): calcd. C 73.37, H 5.07, N 10.07; found C
73.40, H 5.36, N 10.02.
1716 (C=O) cm–1. MS (EI): m/z (%) 173 (4) [M]+, 142 (65), 128
(23), 115 (87), 97 (100). C7H11NO4 (173.17): calcd. C 48.55, H 6.40,
N 8.09; found C 48.22, H 6.06, N 7.76. The spectral data of 3b are
identical to those reported above.
Isoxazole 8b [Ethyl 5-(Hydroxymethyl)-3-isoxazolecarboxylate]:
Isoxazole 8b was prepared according to the general procedure from
1b and propargyl alcohol in ethanol at 80 °C (72 h) using DABCO
(0.10 equiv.) as the base. The solvent was then removed and the
residue purified by chromatography to afford 72 mg (98%) of 8b.
In another experiment carried out according to the general pro-
cedure, the reaction in chloroform at 60 °C (72 h) using DABCO
(0.10 equiv.) as the base afforded the isoxazole 8b in 74% yield.
Eluent: dichloromethane and then dichloromethane/methanol,
Acknowledgments
The authors thank the Ministero dell’Istruzione, Università e
Ricerca (MIUR, Italy) project COFIN-PRIN 2005
– prot.
2005038048 for financial support. Financial support from the Ente
Cassa di Risparmio di Firenze for the purchase of the 400 MHz
NMR instrument is gratefully acknowledged. L. C. thanks the Uni-
versità di Firenze for a doctoral fellowship. E. T. thanks the Uni-
versità di Firenze for a grant. Mrs. B. Innocenti and Mr. M. Passa-
ponti (Università di Firenze) are acknowledged for technical sup-
port.
1
40:1, Rf = 0.29. Clear liquid. H NMR: δ = 1.40 (t, J = 6.8 Hz, 3
H, CH3), 2.19 (br. s, 1 H, OH), 4.42 (q, J = 6.8 Hz, 2 H, OCH2),
4.81 (s, 2 H, CH2OH), 6.66 (t, 4J = 0.8 Hz, 1 H, 4-H) ppm. 13C
NMR: δ = 14.1 (q, CH3), 56.4 (t, CH2OH), 62.3 (t, OCH2), 102.6
(d, C-4), 156.4 (s, C-3), 159.8 (s, C=O), 173.1 (s, C-5) ppm. IR: ν
˜
= 3609 (OH), 1734 (C=O), 1600, 1470 cm–1. MS (EI):[23] m/z (%)
= 171 (4) [M]+, 126 (30) [M – OEt]+, 68 (100). C7H9NO4 (171.15):
calcd. C 49.12, H 5.30, N 8.18; found C 49.22, H 5.44, N 7.96.
[1] For latent functionality in isoxazoles and isoxazolines, see: a)
V. Jäger, P. A. Colinas in Synthetic Applications of 1,3-Dipolar
Cycloaddition Chemistry Toward Heterocycles and Natural
Products (Eds.: A. Padwa, W. H. Pearson), Wiley, New Jersey,
2003, p. 416; b) A. A. Akhrem, F. A. Lakhvich, V. A. Khri-
pach, Chem. Heterocycl. Compd. 1981, 17, 853–868; Khim. Get-
erotsikl. Soedin. 1981, 17, 1155–1173; c) latent functionality in
organic synthesis: D. Lednicer, Adv. Org. Chem. 1972, 8, 17.
[2] For the use of heterocycles in organic synthesis, see: A. I. Mey-
ers, Heterocycles in Organic Synthesis, Wiley, New York, 1974.
[3] a) P. Caramella, P. Grünanger in 1,3-Dipolar Cycloaddition
Chemistry (Ed.: A. Padwa), Wiley, New York, 1984; b) K. B. G.
Torsell, Nitrile Oxides, Nitrones and Nitronates in Organic Syn-
thesis, VCH, Weinheim, 1988; c) V. Jäger, P. A. Colinas in Syn-
thetic Applications of 1,3-Dipolar Cycloaddition Chemistry To-
ward Heterocycles and Natural Products (Eds.: A. Padwa, W. H.
Pearson), Wiley, New Jersey, 2003, p. 368.
Isoxazole 9b [Ethyl 4,5-Bis(hydroxymethyl)-3-isoxazolecarboxylate]:
Isoxazole 9b was prepared according to the general procedure from
1b and 2-butyne-1,4-diol in ethanol at 80 °C (72 h) using DABCO
(0.1 equiv.) as the base. The residue was purified by chromatog-
raphy to afford 9b (25 mg, 29%). The reaction repeated with a
larger excess of ethyl nitroacetate (282 mg, 2.124 mmol, 5 equiv.)
for 90 h afforded 39 mg (46%) of 9b. In another experiment, ac-
cording to the general procedure, the reaction carried out in etha-
nol at 80 °C (72 h) using 4-DMAP (0.10 equiv.) as the base afforded
the isoxazole 9b in 21% yield. Eluent: dichloromethane then
dichloromethane/methanol, 50:1, then dichloromethane/methanol,
1
20:1, Rf = 0.22. Clear oil. H NMR: δ = 1.42 (t, J = 7.2 Hz, 3 H,
CH2CH3), 3.20–3.48 (br. s, 2 H, 2ϫCH2OH), 4.45 (q, J = 7.2 Hz,
2 H, CH2CH3), 4.75 (s, 2 H, CH2OH), 4.80 (s, 2 H, CH2OH) ppm.
13C NMR: δ = 14.1 (q, CH3CH2), 53.8 (t, CH2OH), 55.3 (t,
CH2OH), 62.7 (t, CH3CH2), 117.3 (s, C-4), 154.3 (s, C-3), 161.09
[4] T. Shimizu, Y. Hayashi, K. Teramura, Bull. Chem. Soc. Jpn.
1984, 57, 2531–2534.
[5] a) T. Mukaiyama, T. Hoshino, J. Am. Chem. Soc. 1960, 82,
5339–5342; b) Y. Basel, A. Hassner, Synthesis 1997, 309–312;
c) G. Giacomelli, L. De Luca, A. Porcheddu, Tetrahedron 2003,
59, 5437–5440; d) E. J. Kantorowski, S. P. Brown, M. J. Kurth,
J. Org. Chem. 1998, 63, 5272–5274; e) T. Shimizu, Y. Hayashi,
H. Shibafuchi, K. Teramura, Bull. Chem. Soc. Jpn. 1986, 59,
2827–2831; f) N. Maugein, A. Wagner, C. Mioskowski, Tetra-
hedron Lett. 1997, 38, 1547–1550.
(s, C=O), 169.9 (s, C-5) ppm. IR: ν = 3608 (OH), 1719 (C=O),
˜
1555 cm–1. MS (EI): m/z (%) = 200 (2) [M – H]+, 184 (10) [M–
OH]+, 170 (13), 142 (100), 128 (28), 114 (52), 110 (95). C8H11NO5
(201.18): calcd. C 47.76, H 5.51, N 6.96; found C 47.47, H 5.28, N
7.21.
Scale-Up of the Preparation of Isoxazoline 3b [Ethyl 5-(Hydroxy-
[6] L. Cecchi, F. De Sarlo, F. Machetti, Tetrahedron Lett. 2005, 46,
methyl)-4,5-dihydro-3-isoxazolecarboxylate]: In
a sealed 50 mL
7877–7879.
Schlenk flask DABCO (67 mg, 0.601 mmol, 0.1 equiv.) was dis-
solved in anhydrous ethanol (20 mL). Ethyl nitroacetate (1b)
(2.00 g, 15.0 mmol, 2.5 equiv.) was added to this solution followed
by allyl alcohol (0.349 g, 6.01 mmol). The flask was placed in an
oil bath heated at 80 °C and the mixture stirred (gentle reflux) for
24 h. The solvent was then removed under reduced pressure and
the residue purified by chromatography eluting with diethyl ether/
petroleum ether, 10:1, to yield 874 mg (Rf = 0.94, 1.1 equiv. corre-
sponding to 73% of the expected recovery) of recovered nitroace-
tate (1b) and 968 mg (93% yield, Rf = 0.32) of isoxazoline 3b as a
clear oil containing less than 5% of the corresponding 4-substituted
regioisomer 4b as a clear liquid. A further chromatographic separa-
tion, under the same conditions, allowed the two regioisomers to
be separated. Isoxazole 4b [ethyl 4-(hydroxymethyl)-4,5-dihydro-3-
isoxazolecarboxylate]: 1H NMR: δ = 1.37 (t, J = 7.2 Hz, 3 H,
CH3CH2O), 2.53 (br. s, 1 H, OH), 3.64–3.74 (m, 1 H, 4-H), 3.80–
[7] L. Cecchi, F. De Sarlo, C. Faggi, F. Machetti, Eur. J. Org.
Chem. 2006, 3016–3020.
[8] L. Cecchi, F. De Sarlo, F. Machetti, Eur. J. Org. Chem. 2006,
4852–4860.
[9] For examples of transformations mediated by tertiary amines,
see: S.-K. Tian, Y. Chen, J. Hang, L. Tang, P. McDaid, L.
Deng, Acc. Chem. Res. 2004, 37, 621–631.
[10] Morita–Baylis–Hillman reaction: a) A. B. Baylis, M. E. D.
Hillman, German Patent, DE-2155113, 1972 [Chem. Abstr.
1972, 77, 34174q]; b) D. Basavaiah, A. J. Rao, T. Satyanaray-
ana, Chem. Rev. 2003, 103, 811–892; Stille coupling: c) J.-H.
Li, Y. Liang, D.-P. Wang, W.-J. Liu, Y.-X. Xie, D.-L. Yin, J.
Org. Chem. 2005, 70, 2832–2834; Suzuki–Miyaura cross-coup-
ling reaction: d) J.-H. Li, W.-J. Liu, Org. Lett. 2004, 6, 2809–
2811; Heck reaction, cyanation of ketones: e) S.-K. Tian, R.
Hong, L. Deng, J. Am. Chem. Soc. 2003, 125, 9900–9901; ring-
opening of aziridines: f) J. Wu, X. Sun, Y. Li, Eur. J. Org. Chem.
4358
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© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 4352–4359

Isoxazoles and Isoxazolines by 1,3-Dipolar Cycloaddition
FULL PAPER
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[20] M. J. Fray, E. J. Thomas, Tetrahedron 1984, 40, 673–680.
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[22] T. Benincori, E. Brenna, F. Sannicolo, J. Chem. Soc. Perkin
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[11] The decomposition of nitro compounds 1a–e under our experi-
mental conditions has not been examined in detail. However,
mainly benzoic acid from benzoylnitromethane and ethanol
from ethyl nitroacetate were identified by 1H NMR spec-
troscopy, in addition to minor amounts of nitromethane.
[12] P. Caldirola, M. De Amici, C. De Micheli, P. A. Wade, D. T.
Price, J. F. Boreznak, Tetrahedron 1986, 42, 5267–5272.
[13] R. Warsinsky, E. Steckhan, J. Chem. Soc. Perkin Trans. 1 1994,
2027–2037.
[23] A signal at a higher m/z value (296) in the mass spectrum indi-
cates that transesterification occurred upon heating (250 °C in-
jection temperature).
[14] K. S. Lee, Y. K. Kang, K. H. Yoo, D. C. Kim, K. J. Shin, Y.-S.
Paikb, D. J. Kima, Bioorg. Med. Chem. Lett. 2005, 15, 231–
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Received: March 28, 2007
[15] M. J. Fray, E. J. Thomas, Tetrahedron 1984, 40, 673–680.
[16] W. J. Pitts, J. Wityak, J. M. Smallheer, A. E. Tobin, J. W. Jetter,
J. S. Buynitsky, P. P. Harlow, K. A. Solomon, M. H. Corjay,
Published Online: July 10, 2007
Eur. J. Org. Chem. 2007, 4352–4359
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4359