Vinylogous nitroaldol (Henry) reaction using 3,5-diethyl-4-nitroisoxazole and carbonyl compounds

Article abstract of DOI:10.1016/j.tet.2008.11.089

3,5-Diethyl-4-nitroisoxazole reacted with carbonyl compounds in the presence of an amine catalyst. The vinylogous nitroaldol adducts were isolated in good yields.

Full text of DOI:10.1016/j.tet.2008.11.089

Tetrahedron 65 (2009) 990–997
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Vinylogous nitroaldol (Henry) reaction using 3,5-diethyl-4-nitroisoxazole
and carbonyl compounds
*
Mauro F.A. Adamo , Surisetti Suresh
Centre for Synthesis and Chemical Biology (CSCB), Department of Pharmaceutical and Medicinal Chemistry, The Royal College of Surgeons in Ireland,
123 St. Stephen’s Green, Dublin 2, Dublin, Ireland
a r t i c l e i n f o
a b s t r a c t
Article history:
3,5-Diethyl-4-nitroisoxazole reacted with carbonyl compounds in the presence of an amine catalyst. The
vinylogous nitroaldol adducts were isolated in good yields.
Received 5 September 2008
Received in revised form 8 November 2008
Accepted 27 November 2008
Available online 3 December 2008
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
4-Nitroisoxazoles
Henry reaction
Vinylogous nitroaldol
1. Introduction
in the presence of sodium ethoxide;5 3-methoxy-4-methyl-5-nitro-
benzoic acid methyl ester reacted with an aliphatic aldehyde in the
The Henry or nitroaldol reaction is one of the important re-
actions in organic synthesis.1 Essentially a coupling between a car-
key step of the synthesis of mitosene-based antitumour agents.6–8
The processes employing ortho-nitrotoluenes were based on
the remarkable acidity of the ortho-methyl group that is activated
by conjugation with the nitro group. In previous reports, we
have shown that 3,5-dimethyl-4-nitroisoxazole 7 (R¼H) (Scheme
2) is a useful building block that could be employed for the
synthesis of 5-heteroarylethenylisoxazoles,9 spiroisoxazolines,10
3-heteroarylpropionic acids,11 3-indolepropionic acids,12 isox-
azolopyridones, pyrazolopyridones,13 isoxazoloazepinones, pyr-
azoloazepinones14 and 3-arylglutaric acids.15 In these syntheses,
isoxazole 7 was efficiently deprotonated by secondary or tertiary
amines and the resulting nitro enolate reacted with various elec-
trophiles. Considering the similarity between compounds 4 and 7,
we posed the question of whether the latter could be employed in
bonyl compound 2 and an alkylnitro group 1 bearing
(Scheme 1), this reaction gives a
-nitroalcohol moiety 3,2 that
served as starter for the generation of several compounds including
nitroalkenes, -aminoalcohols, -hydroxy carbonyl compounds
and -nitro ketones. In this process two new asymmetric centres
a-hydrogens
b
b
a
b
are generated at the new carbon–carbon juncture. The Henry re-
action is an example of a classical organic reaction, which has un-
dergone extensive development.1d
OH
O
O2N
∗
∗
R
+
R'
R'
R
NO2
3
1
2
NO2
NO2
O
NaOEt
OH
Ph
Scheme 1. Nitroaldol (Henry) reaction.
+
Ph
Several variations of the Henry reaction such as intramolecular3
or aza-Henry4 processes have received considerable attention.
Additionally, a few examples of vinylogous Henry reaction in-
volving ortho-nitrotoluenes have been reported.5–8 In particular,
2-nitrotoluene 4 (Scheme 2) underwent addition to benzaldehyde
4
5
6
'active'
NO2
R
NO
R
R
O
2 OH
Ph
Base
?
'active'
N
N
Ph
O
O
9
R
7 R= H
5
8 R = CH3
Scheme 2. Vinylogous aldol (Henry) reaction.
* Corresponding author. Tel.: þ353 1 4022208; fax: þ353 1 4022168.
E-mail address: madamo@rcsi.ie (M.F.A. Adamo).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.11.089

M.F.A. Adamo, S. Suresh / Tetrahedron 65 (2009) 990–997
991
a vinylogous Henry reaction (Scheme 2). Resulting adducts 9 would
contain several chemo-differentiable functionalities and could be
subsequently employed to generate chemical diversity. Addition-
ally, although a few reports appeared describing a vinylogous ap-
proach to the Henry reaction,5–8 a comprehensive methodological
study of this transformation has not been reported yet. With these
goals in mind we set out to develop a vinylogous Henry reaction
using 4-nitro-5-alkylisoxazoles 7 and 8.
Several amines were used as catalysts (Table 2): tertiary amines
were superior catalysts compared to secondary ones (compare
entries 1 and 5, Table 2) and triethylamine was the best. When
secondary amines were used, compound 13 was obtained in low
yields along with a similar amount of alkene 14 (Table 2, entries 3, 5
and 13) that was formed as a single isomer. The stereochemistry of
14 was assigned by NOE studies. Significant enhancement was
observed between the CH3 and the ]CH. Non-nitrogenous base
PPh3 was a poor catalyst. Compound 13 was obtained as 1:1 mix-
ture of syn and anti diastereomers. This occurred similarly carrying
out the reaction either at room temperature or at 0 ꢀC. In order to
improve the diastereoselectivity we have run the reaction at low
temperature and in the presence of lithium bases. Hence 8 was
treated with a stoichiometric amount of LDA and at temperatures of
ꢁ78 ꢀC or ꢁ30 ꢀC then the nitronate formed was quenched by the
addition of excess aldehyde. This procedure gave product 13 in 30%
yield in a similar 1:1 ratio of syn and anti diastereoisomers. The use
of chiral amines like quinine, hydroquinine or (S)-1-(2-pyrrolidi-
nylmethyl)pyrrolidine, that often have been shown guiding the
stereochemical outcome of related processes,18 led to 1:1 di-
astereomeric mixture of 13 as obtained for Et3N. We have analyzed
the samples of 13 obtained using chiral amines by HPLC (on Chir-
alcel OD, Chiralcel OJ and Chiralpak AD) to establish whether an
enantiomeric excess within each diastereoisomer was present, but
no enantiomeric enrichment was observed.
2. Results and discussion
We started our investigation by reacting 3,5-dimethyl-4-nitro-
isoxazole 7 and aldehydes. We and others have shown that reacting
isoxazole 7 with aromatic aldehydes 5 (Scheme 2) in the presence
of organic bases and in hot solvents generated 3-methyl-4-nitro-5-
styryl isoxazoles in excellent yields.9,16 This reaction run faster
under the catalysis of a secondary amine9 and proceeded through
the formation of aldol like adduct 10 (Scheme 3) followed by
elimination of water.
NO2
NO2
OH
PhCHO/Et3N
N
N
MeOH, rt, 24 h
Ph
32%
O
O
10
7
The scope of reaction was then studied by reacting various
carbonyl compounds with isoxazole 8. Data collected indicated that
carbonyl compounds of wide nature gave the corresponding alka-
nol products in moderate to excellent isolated yields (Table 3).
Reactive aldehydes, conjugated with an electron withdrawing
group, gave best yields of Henry adducts 16a–c (Table 3, entries 2–
4). Aromatic aldehydes bearing electron donating groups gave de-
sired compounds 16d, 16e in moderate yields (Table 3, entries 5 and
6). These observations are in line with other reports on the Henry
reaction.1,2 Heteroaromatic aldehydes such as 2-furaldehyde (Table
Scheme 3. Reaction of 3,5-dimethyl-4-nitroisoxazole and benzaldehyde.
In order to intercept adduct 10 (Scheme 3), we have reacted 7
(1 equiv) with benzaldehyde (2 equiv) in the presence of triethyl-
amine (0.3 equiv) at room temperature. In this experiment, we
have isolated product 10 in 32% yield (Scheme 3) together with 60%
of unreacted isoxazole 7. Variation of solvent, nature and amount of
the amine catalyst and reaction stoichiometry did not improve the
yields of 10.
This set of experiments set a proof of principle for the desired
vinylogous nitroaldol reaction. To substantiate this finding, we have
prepared 3,5-diethyl-4-nitroisoxazole 8 (Scheme 4). Compound 8
was obtained in two steps from commercially available 3,5-hepta-
nedione 11. Condensation of 11 with hydroxylamine furnished 3,5-
diethylisoxazole 12 that was subsequently nitrated to obtain
desired 8.17
Compound 8 was dissolved in methanol and reacted with
2 equiv of freshly distilled benzaldehyde 5 in the presence of
30 mol % of triethylamine. Under these conditions, product 13 was
formed in excellent yields (Table 1, entry 1). Compound 13 was
obtained as a 1:1 mixture of diastereoisomers. In order to improve
the diastereoselectivity of this process a solvent study was un-
dertaken (Table 1). This study revealed the following facts: (a) ex-
periments run at higher concentration of reactants (10 M) gave
high yields irrespectively of the nature of the solvent used; (b)
experiments run at higher concentration (10 M) gave compound 13
as a 1:1 mixture of diastereoisomers; (c) experiments run at lower
concentration (1 M) gave decreased yields of 13; (d) experiments
run at lower concentration (1 M) in non-polar aprotic solvents
(Table 1, entries 3–7) gave 13 as a 7:3 mixture of diastereoisomers;
(e) highest yield of 13 was obtained when reaction was carried out
in methanol (Table 1, entry 1). It was noted that the use of at least
30 mol % of amine, and excess aldehyde (2 equiv) was required to
ensure high conversion.
3, entry 7), a,b-unsaturated aldehydes such as trans cinnamalde-
hyde (Table 3, entry 8), ethyl glyoxalate (Table 3, entry 9) and
methyl phenylglyoxalate (Table 3, entry 10) were also good sub-
strates. Importantly, the reaction of 8 with cinnamaldehyde fur-
nished exclusively the expected aldol product 16g, uncontaminated
by the alternative conjugate addition adduct. The reaction of 8 with
isobutyraldehyde run at 10 M concentration of reactants furnished
the corresponding alkanol product 16j in low yield (21%) and in
good diastereoselectivity (81:19). In order to increase the yield, this
reaction was conducted at high concentration (10 M) and pro-
longed reaction times. Delightfully, under these conditions, signif-
icant increase of the yield was observed with no change of the
diastereoselectivity (Table 3, entry 11). Isovaleraldehyde, n-hep-
taldehyde and cyclohexane carbaldehyde reacted with 8 giving the
corresponding products 16k–m in excellent yields and good dia-
stereoselectivity (Table 3, entries 12–14). The reaction of 2-ethyl-
butyraldehyde gave the alkanol 16n product in moderate yield and
with good selectivity (Table 3, entry 15). In the case of piv-
alaldehyde product 16o was isolated in low yield but in high dia-
stereoselectivity (Table 3, entry 16). syn and anti diastereomers of
16i–k, 16m, 16n could be separated using flash column chroma-
tography. This was an important point as the separation of syn and
anti diastereomers of 13, 16a–h, 16l, 16o was not possible. We have
carried out NOE experiments to assign a syn or an anti relative
H
O
O
NO2
H2SO4/HNO3
NH2OH.HCl/Na2CO3
N
0-5 °C, then 100 °C, 2 h
N
MeOH/H2O (1:2)
reflux, 8 h
O
O
11
12
8
Scheme 4. Synthesis of 3,5-diethyl-4-nitroisoxazole 8.

992
M.F.A. Adamo, S. Suresh / Tetrahedron 65 (2009) 990–997
Table 1
Reaction of 3,5-diethyl-4-nitroisoxazole 8 and benzaldehyde 5 in different solvents
NO2
O
NO
2 OH
Et3N
Solvent, rt, 24 h
+
N
N
H
Ph
Ph
O
O
8
5
13
Entry
Solvent
Yield of 13
at 10
dr
Yield of 13a
at 1
dr
M concn (%)
M concn (%)
1
2
3
4
5
6
7
8
Methanol
Diethylether
Toluene
Petroleum ether
n-Hexane
Cyclohexane
n-Heptane
94
63
59
61
68
73
60
78
79
72
47
82
68
53:47
58:42
51:49
51:49
50:50
50:50
54:46
51:49
53:47
50:50
53:47
50:50
52:48
94
57
39
18
44
15
40
d
d
d
d
d
d
53:47
58:42
63:37
69:31
67:33
70:30
69:31
d
Ethanol
9
tert-Butanol
Dimethylsufoxide
Acetonitrile
Tetrahydrofuran
1,4-Dioxane
d
10
11
12
13
d
d
d
d
configuration to the 16i and epi-16i diastereomers, but these ex-
periments were inconclusive.
Table 1, entries 1–7); unfortunately under these conditions
the reaction was slow and limited conversion was observed; (b) the
product distribution was under thermodynamic control when the
vinylogous nitroaldol reaction was carried out at higher concen-
tration (1 M) and in protic and apolar solvents (see Tables 1 and 3).
In the latter case, the diastereoselectivity depended on the relative
thermodynamic stability of the two diastereoisomers. This was
particularly evident for compounds 16 arising from aliphatic alde-
hydes in which the steric demand of R1 and R2 groups was re-
markably different (Table 3, entries 13–16).
The low level of diastereoselectivity observed for some of
compounds 16 arose from the acidity of the methine group in
compounds 13 and 16a–i. This was demonstrated by dissolving
pure 16i and epi-16i in methanol (1 M) and reacting them with
triethylamine (30 mol %) for 4 h at room temperature (Scheme 5).
The crude mixtures were analyzed by 1H NMR that confirmed the
presence of 16i and epi-16i in both samples. The two experiments
furnished the same 6:4 mixture of 16i and epi-16i. This experiment
demonstrated that 16i and epi-16i established equilibrium with
nitronate 17 when the base was present. Alkene 18, arising from
a base promoted dehydration of 16i and epi-16i, was also identified
in these experiments (Scheme 5). Detection of 18 gave additional
support to the presence of nitronate 17. This data pointed out the
following facts: (a) the product distribution was under kinetic
control only when the vinylogous nitroaldol reaction was carried
out at lower concentration (1 M) and in aprotic apolar solvents (see
In conclusion, we have described a novel variant of the Henry
reaction in which a new bond between 3,5-diethyl-4-nitroisoxazole
8 and carbonyl compounds was formed. This reaction worked un-
der the catalysis of a simple and inexpensive triethylamine and
gave a novel class of b-heteroaryl alkanol products in high yields.
Application of this novel concept to the synthesis of naturally oc-
curring compounds and efforts aimed at controlling the stereo-
chemistry are in progress.
Table 2
Reaction of 3,5-diethyl-4-nitroisoxazole 8 and benzaldehyde 5 using different bases
NO2
O
NO
NO2
2 OH
base
Solvent, rt, 24 h
+
+
N
N
N
Ph
H
Ph
O
8
O
13
O
5
14
Ph
Entry
Base
Yield of
Yield of
13 (%)
14 (%)
1
2
3
4
5
6
7
8
Triethylamine
92
49
26
52
21
19
79
17
0
51
71
25
25
d
d
30
d
13
d
d
d
d
d
d
d
20
4-(N,N-Dimethylamino)pyridine
N,N,N0-Trimethylethylenediamine
1,4-Diazabicyclo[2.2.2]octane
Piperidine
1,5-Diazabicyclo[4.3.0]non-5-ene
N,N-Diisopropylethylamine
1,3-Imidazole
Triphenylphosphine
Quinine
Hydroquinine
N-Methylmorpholine
9
10
11
12
13
(S)-1-(2-Pyrrolidinylmethyl)pyrrolidine

M.F.A. Adamo, S. Suresh / Tetrahedron 65 (2009) 990–997
993
Table 3
carried out using silica gel 60 (0.040–0.063 mm, 230–400 mesh) as
the stationary phase. Thin layer chromatography was carried out on
aluminium backed plates pre-coated with silica gel 60, which were
visualized by quenching of UV fluorescence (lmax¼254 nm) or by
staining with either 10% w/v ammonium molybdate in 2 M sulfuric
acid or basic potassium permanganate solution (followed by heat)
as appropriate. Retention factors (Rf) are reported to ꢂ0.05.
Reaction of 3,5-diethyl-4-nitroisoxazole with various carbonyl compounds
NO2
NO
2 OH
O
Et3N
+
R1
R2
N
N
R2
MeOH, rt, 24 h
O
O
R1
8
15
13 and 16a-o
Entry
R1
R2
Concn
(M)
Time
(h)
Yielda of
13 and 16
(%)
dr
3.2. Preparation of 3,5-diethyl-4-nitroisoxazole 8
1
2
3
4
5
6
7
8
C6H5
p-ClC6H4
H
H
H
H
H
H
H
H
H
C6H5
H
H
H
H
H
H
1
1
1
1
1
1
1
1
1
24
24
24
24
24
24
24
24
24
24
72
72
72
72
72
72
(13) 92
53:47b
53:47b
51:49b
54:46b
59:41b
55:45b
60:40b
52:48b
62:38b
61:39c
79:21c
72:28c
88:12d
74:26c
86:14c
90:10c
To a solution of hydroxylamine hydrochloride (7.3 g, 105 mmol)
in methanol/water (50:100 mL) was added sodium carbonate
(5.3 g, 50 mmol) in portions and at room temperature. To this so-
lution was added 3,5-heptanedione 11 (13.4 g, 105 mmol) and re-
action mixture was refluxed for 8 h. After this time, the reaction
mixture was allowed to reach room temperature and extracted
using diethylether (2ꢃ200 mL). The organic layer was washed with
brine (50 mL), dried over anhydrous Na2SO4, filtered and evapo-
rated under reduced pressure to obtain 3,5-diethylisoxazole 12 in
quantitative yield. This material was pure enough to be carried
through the next step without further purification.
(16a) 78
(16b) 88
(16c) 60
(16d) 49
(16e) 44
(16f) 69
(16g) 45
(16h) 52
(16i) 70
(16j) 83
(16k) 86
(16l) 89
(16m) 96
(16n) 46
(16o) 15
p-CNC6H4
p-NO2C6H4
p-MeC6H4
p-OMeC6H4
2-Furyl
CH]CHC6H5
COOC2H5
COOCH3
CH(CH3)2
CH2CH(CH3)2
CH2(CH2)4CH3
Cyclohexyl
CH(C2H5)2
C(CH3)3
9
10
11
12
13
14
15
16
1
10
10
10
10
10
10
A 250 mL reaction flask fitted with a thermometer was charged
with H2SO4 concd (26 mL) and cooled to 0 ꢀC and then were se-
quentially added 3,5-diethylisoxazole (12.5 g, 100 mmol), HNO3
concd (10 mL) and H2SO4 concd (40 mL). The addition of 3,5-
diethylisoxazole and further amounts of acids were carried out
drop wise in order to keep the temperature in the range 0–5 ꢀC.
When the addition was completed, the reaction mixture was
heated at 100 ꢀC for 2 h, then allowed to reach room temperature
and poured in ice. The organic phase was separated, diluted in ethyl
acetate (300 mL), washed with water (2ꢃ100 mL), then brine
(50 mL), dried over anhydrous Na2SO4, filtered and concentrated
under reduced pressure. The crude product was distilled under
vacuum (100 ꢀC at 10–20 mm/Hg) to give 12.71 g of pure 3,5-
diethyl-4-nitroisoxazole 8 (71% yield). Colourless liquid, Rf¼0.7
(petroleum ether/EtOAc, 90:10), IR (Neat): 2989 w, 1586 s; 1H NMR
(400 MHz, CDCl3): 1.34 (CH3, t, 3H, J¼7.6 Hz), 1.40 (CH3, t, 3H,
a
Yields are for isolated products.
Diastereomeric ratios were estimated using 1H NMR data.
The diastereomers were separated using flash chromatography.
Diastereomeric ratio was estimated using 13C NMR data.
b
c
d
3. Experimental section
3.1. General experimental
1H and 13C NMR spectra were recorded on a 200 or a 400 MHz
spectrometers at ambient temperatures. 1H NMR spectral assign-
ments are supported by 1H–1H COSY and 13C–1H COSY where
necessary. For 1H NMR recorded in CDCl3 chemical shifts (dH) are
quoted in parts per million (ppm) and are referenced to the residual
solvent peak. The following abbreviations are used: s, singlet, d,
doublet, t, triplet, dd, doublet of doublets, dt, doublet of triplets, tt,
triplet of triplets, m, multiplet and br, broad. Coupling constants (J)
were recorded in hertz (Hz) to the nearest 0.5 Hz. Carbon spectra
are supported by DEPT analysis where necessary. Infrared (IR)
spectra were recorded as thin films between NaCl plates. Absorp-
tion maximum (nmax) was reported in wave numbers (cmꢁ1) and
only selected peaks are reported. The following abbreviations are
used: w, weak, m, medium, s, strong and br, broad. High resolution
mass spectra were obtained on a Waters Micro mass LCT and low
resolution mass spectra were recorded on Waters Micro mass
Quattro LCMS spectrometers at 70 eV. Flash chromatography was
J¼7.6 Hz), 3.00 (CH2, q, 2H, J¼7.6 Hz), 3.24 (CH2, q, 2H, J¼7.6 Hz); 13
C
NMR (100 MHz, CDCl3): 10.4 (CH3), 11.3 (CH3), 19.8 (CH2), 21.7
(CH2), 139.1 (C–NO2), 160.1 (C]N), 176.5 (C–O); HRMS: m/z found
[Mþ] 170.0692, C7H10N2O3 requires 170.0691; m/z: 170 (100%, Mþ).
3.3. Preparation of 2-(3-methyl-4-nitro-isoxazol-5-yl)-1-
phenyl-ethanol 10
In a round bottomed flask were put 3,5-dimethyl-4-nitro-
isoxazole 7 (284 mg, 2 mmol), triethylamine (60 mg, 0.6 mmol) and
methanol (2 mL) and the reaction mixture stirred for 15 min. Then
benzaldehyde (424 mg, 4 mmol) was added and the solution stirred
for 24 h at room temperature. After this time, the solvent was
O
N
NO
2 OH
+
NO
2 OH
O
+
OH
Et3N
Et3NH
Et3N
N
Ph
N
N
O
Ph
COOMe
Ph
COOMe
17
COOMe
O
O
16i
epi-16i
-H2O
NO2 Ph
N
O
COOMe
18
Scheme 5. Reaction of pure diastereomer of 16i with Et3N.

994
M.F.A. Adamo, S. Suresh / Tetrahedron 65 (2009) 990–997
evaporated and the oil so obtained subjected to column chroma-
tography on silica gel [petroleum ether and ethyl acetate (95:5)] to
give 10 as a colourless viscous oil, 159 mg, 32%, Rf¼0.3 (petroleum
ether/EtOAc, 90:10), IR (KBr): 3430 br, 2989 w, 1598 s; 1H NMR
(400 MHz, CDCl3): 2.21 (OH, br s, 1H), 2.48 (CH3, s, 3H), 3.48 (CH2,
dd, 1H, J1¼4 Hz, J2¼4.4 Hz), 3.59 (CH2, dd, 1H, J1¼9.2 Hz, J2¼8.8 Hz),
5.15–5.19 (CH, m, 1H), 7.25–7.28 (Ar–H, m, 2H), 7.30–7.35 (Ar–H, m,
3H); 13C NMR (100 MHz, CDCl3): 11.7 (CH3), 37.3 (CH2), 71.7 (CH),
125.5 (Ar–CH), 128.6 (Ar–CH), 128.9 (Ar–CH), 142.2 (Ar–C), 155.7
(C]N), 172.0 (]C–O); HRMS: m/z found [Mþ] 248.0781,
C12H12N2O4 requires 248.0797; m/z: 248 (100%, Mþ).
CH3, m, 2H), 4.96 (CH–OH, d, 1H, J¼9.2 Hz), 5.13 (CH–OH, d, 1H,
J¼5.6 Hz), 7.42–7.45 (Ar–H, m, 4H), 7.54 (Ar–H, d, 2H, J¼8 Hz),
7.59 (Ar–H, d, 2H, J¼8 Hz); 13C NMR (100 MHz, CDCl3): 11.0
(CH2–CH3), 11.1 (CH2–CH3), 11.2 (CH–CH3), 14.5 (CH–CH3), 19.8
(CH2–CH3), 19.9 (CH2–CH3), 40.5 (CH–CH3), 40.8 (CH–CH3), 74.1
(CH–OH), 75.8 (CH–OH), 111.6 (Ar–C), 112.2 (Ar–C), 118.4 (Ar–
C^N), 118.6 (Ar–C^N), 126.8 (Ar–CH), 127.5 (Ar–CH), 129.2 (C–
NO2), 130.3 (C–NO2), 132.3 (Ar–CH), 132.5 (Ar–CH), 146.6 (Ar–C),
146.7 (Ar–C), 160.1 (C]N), 160.1 (C]N), 175.3 (]C–O), 175.6
(]C–O); HRMS: m/z found [MꢁH]þ 300.0988, C15H14N3O4 re-
quires 300.0984; m/z: 300 (100%, MꢁHþ).
3.4. General experimental procedure for the synthesis of
compounds 13 and 16a–i (Table 3)
3.4.4. 2-(3-Ethyl-4-nitro-isoxazol-5-yl)-1-(4-nitro-phenyl)-
propan-1-ol 16c
Pale yellow viscous oil, 386 mg, 60%, Rf¼0.1 (CHCl3/MeOH, 98:2),
IR (KBr): 3436 br, 2990 w, 1598 s; 1H NMR (400 MHz, CDCl3): 1.15
(CH–CH3, d, 3H, J¼7.2 Hz), 1.24 (CH2–CH3, t, 3H, J¼7.2 Hz), 1.27
(CH2–CH3, t, 3H, J¼7.6 Hz), 1.32 (CH–CH3, d, 3H, J¼7.2 Hz), 2.45–2.47
(OH, m, 2H), 2.88–2.97 (CH2–CH3, m, 4H), 4.07–4.16 (CH–CH3, m,
2H), 5.02–5.06 (CH–OH, m, 1H), 5.21–5.23 (CH–OH, m, 1H), 7.49–
7.52 (Ar–H, m, 4H), 8.12–8.19 (Ar–H, m, 4H); 13C NMR (100 MHz,
CDCl3): 11.0 (CH2–CH3), 11.1 (CH2–CH3), 14.5 (CH–CH3), 19.7 (CH2–
CH3), 19.8 (CH2–CH3), 40.5 (CH–CH3), 40.7 (CH–CH3), 74.1 (CH–OH),
75.6 (CH–OH), 123.7 (Ar–CH), 123.9 (Ar–CH), 126.9 (Ar–CH), 127.6
(Ar–CH), 147.6 (Ar–C), 147.9 (Ar–C), 148.1 (Ar–C), 148.3 (Ar–C), 160.0
(C]N), 160.1 (C]N), 175.1 (]C–O), 175.4 (]C–O); HRMS: m/z
found [MꢁH]þ 320.0878, C14H14N3O6 requires 320.0883; m/z: 320
(100%, MꢁHþ).
3,5-Diethyl-4-nitroisoxazole 8 (340 mg, 2 mmol) and triethyl-
amine (60 mg, 0.6 mmol) were dissolved in methanol (2 mL) and
the contents stirred for 15 min. Then a carbonyl compound
(4 mmol) 5 or 15a–i was added to the reaction mixture and this
stirred for 24 h at room temperature. After this time, the solvent
was evaporated and the crude material so obtained purified by
flash column chromatography on silica gel [petroleum ether and
ethyl acetate (95:5)] to give 13 and 16a–i.
3.4.1. 2-(3-Ethyl-4-nitro-isoxazol-5-yl)-1-phenyl-propan-1-ol 13
Colourless viscous oil, 508 mg, 92%, Rf¼0.3 (petroleum ether/
EtOAc, 90:10), IR (KBr): 3424 br, 2986 w, 1597 s; 1H NMR (400 MHz,
CDCl3): 1.07 (CH–CH3, d, 3H, J¼8 Hz),1.18 (CH2–CH3, t, 3H, J¼7.2 Hz),
1.26 (CH2–CH3, t, 3H, J¼7.2 Hz), 1.35 (CH–CH3, d, 3H, J¼7.2 Hz), 2.30
(OH, s, 1H), 2.37 (OH, s, 1H), 2.83 (CH2–CH3, q, 2H, J¼7.2 Hz), 2.91
(CH2–CH3, q, 2H, J¼7.6 Hz), 4.07–4.14 (CH–CH3, m, 2H), 4.84 (CH–
OH, d,1H, J¼9.6 Hz), 4.99 (CH–OH, d,1H, J¼6.0 Hz), 7.19–7.22 (Ar–H,
m, 5H), 7.29–7.32 (Ar–H, m, 5H); 13C NMR (100 MHz, CDCl3): 11.1
(CH2–CH3), 11.2 (CH2–CH3), 12.0 (CH–CH3), 14.7 (CH–CH3), 19.7
(CH2–CH3), 19.9 (CH2–CH3), 40.6 (CH–CH3), 40.9 (CH–CH3), 75.4
(CH–OH), 76.7 (CH–OH), 125.8 (Ar–CH), 126.7 (Ar–CH), 128.2 (Ar–
CH), 128.5 (Ar–CH), 128.7 (Ar–CH), 128.8 (Ar–CH), 141.0 (Ar–C),
141.3 (Ar–C), 159.9 (C]N), 160.0 (C]N), 176.1 (]C–O), 176.3 (]C–
O); HRMS: m/z found [MꢁH]þ 275.1028, C14H15N2O4 requires
275.1032; m/z: 275 (100%, MꢁHþ).
3.4.5. 2-(3-Ethyl-4-nitro-isoxazol-5-yl)-1-p-tolyl-propan-1-ol 16d
Pale yellow viscous oil, 283 mg, 49%, Rf¼0.3 (petroleum ether/
EtOAc, 90:10), IR (KBr): 3429 br, 2991 w, 1596 s; 1H NMR (400 MHz,
CDCl3): 1.02 (CH–CH3, d, 3H, J¼7.2 Hz), 1.14 (CH2–CH3, t, 3H,
J¼7.2 Hz), 1.21 (CH2–CH3, t, 3H, J¼7.2 Hz), 1.30 (CH–CH3, d, 3H,
J¼7.6 Hz), 2.19 (Ar–CH3, s, 3H), 2.26 (Ar–CH3, s, 3H), 2.56 (OH, s, 1H),
2.70 (OH, s, 1H), 2.77 (CH2–CH3, q, 2H, J¼7.2 Hz), 2.86 (CH2–CH3, q,
2H, J¼7.2 Hz), 3.95–4.07 (CH–CH3, m, 2H), 4.74 (CH–OH, d, 1H,
J¼9.2 Hz), 4.88 (CH–OH, d, 1H, J¼5.6 Hz), 6.97 (Ar–H, d, 2H, J¼8 Hz),
7.04–7.09 (Ar–H, m, 4H), 7.14 (Ar–H, d, 2H, J¼8.4 Hz); 13C NMR
(100 MHz, CDCl3): 11.1 (CH2–CH3), 12.1 (CH2–CH3), 14.7 (CH–CH3),
19.7 (CH2–CH3), 19.9 (CH2–CH3), 21.1 (Ar–CH3), 21.2 (Ar–CH3), 40.6
(CH–CH3), 40.9 (CH–CH3), 75.2 (CH–OH), 76.5 (CH–OH), 125.8 (Ar–
CH), 126.6 (Ar–CH), 129.1 (Ar–CH), 129.4 (Ar–CH), 137.8 (Ar–C),
138.2 (Ar–C), 138.5 (Ar–C), 159.9 (C]N), 160.0 (C]N), 176.3 (]C–
O), 176.6 (]C–O); HRMS: m/z found [MꢁH]þ 289.1181, C15H17N2O4
requires 289.1188; m/z: 289 (100%, MꢁHþ).
3.4.2. 1-(4-Chloro-phenyl)-2-(3-ethyl-4-nitro-isoxazol-5-yl)-
propan-1-ol 16a
Pale yellow viscous oil, 482 mg, 78%, Rf¼0.2 (petroleum
ether/EtOAc, 90:10), IR (KBr): 3432 br, 2989 w, 1599 s; 1H NMR
(400 MHz, CDCl3): 1.08 (CH–CH3, d, 3H, J¼7.2 Hz), 1.21 (CH2–CH3,
t, 3H, J¼7.6 Hz), 1.26 (CH2–CH3, t, 3H, J¼7.6 Hz), 1.33 (CH–CH3, d,
3H, J¼6.8 Hz), 2.39 (OH, s, 1H), 2.43 (OH, s, 1H), 2.83–2.95 (CH2–
CH3, m, 4H), 4.01–4.09 (CH–CH3, m, 2H), 4.84 (CH–OH, d, 1H,
J¼9.2 Hz), 5.01 (CH–OH, d, 1H, J¼5.6 Hz), 7.20–7.26 (Ar–H, m,
4H), 7.28–7.31 (Ar–H, m, 4H); 13C NMR (100 MHz, CDCl3): 11.2
(CH2–CH3), 11.8 (CH2–CH3), 14.2 (CH–CH3), 14.7 (CH–CH3), 19.8
(CH2–CH3), 19.9 (CH2–CH3), 40.6 (CH–CH3), 40.8 (CH–CH3), 74.6
(CH–OH), 76.1 (CH–OH), 127.3 (Ar–CH), 128.1 (Ar–CH), 128.7 (Ar–
CH), 129.0 (Ar–CH), 133.9 (Ar–C), 134.5 (Ar–C), 139.6 (Ar–C),
139.8 (Ar–C), 160.0 (C]N), 160.1 (C]N), 175.8 (]C–O), 176.0
(]C–O); HRMS: m/z found [MꢁH]þ 309.0651, C14H14ClN2O4 re-
quires 309.0642; m/z: 309 (100%, MꢁHþ).
3.4.6. 2-(3-Ethyl-4-nitro-isoxazol-5-yl)-1-(4-methoxy-phenyl)-
propan-1-ol 16e
Pale brown viscous oil, 268 mg, 44%, Rf¼0.1 (CHCl3/MeOH, 99:1),
IR (KBr): 3427 br, 2992 w, 1596 s; 1H NMR (400 MHz, CDCl3): 1.07
(CH–CH3, d, 3H, J¼7.2 Hz), 1.20 (CH2–CH3, t, 3H, J¼7.2 Hz), 1.28
(CH2–CH3, t, 3H, J¼7.2 Hz), 1.38 (CH–CH3, d, 3H, J¼7.2 Hz), 2.04 (OH,
s, 1H), 2.11 (OH, s, 1H), 2.84 (CH2–CH3, q, 2H, J¼7.6 Hz), 2.94 (CH2–
CH3, q, 2H, J¼7.6 Hz), 3.71 (Ar–OCH3, s, 3H), 3.76 (Ar–OCH3, s, 3H),
4.07–4.13 (CH–CH3, m, 2H), 4.81 (CH–OH, d, 1H, J¼9.6 Hz), 4.96
(CH–OH, d, 1H, J¼6.4 Hz), 6.75 (Ar–H, d, 2H, J¼8.8 Hz), 6.84–6.86
(Ar–H, m, 2H), 7.15 (Ar–H, d, 2H, J¼6.8 Hz), 7.25 (Ar–H, d, 2H,
J¼4.8 Hz); 13C NMR (100 MHz, CDCl3): 11.2 (CH2–CH3), 12.6 (CH2–
CH3), 14.8 (CH–CH3), 19.8 (CH2–CH3), 19.9 (CH2–CH3), 40.7
(CH–CH3), 40.9 (CH–CH3), 55.3 (Ar–OCH3), 55.4 (Ar–OCH3), 75.3
(CH–OH), 76.6 (CH–OH), 113.9 (Ar–CH), 114.2 (Ar–CH), 127.2 (Ar–
CH), 127.9 (Ar–CH), 133.2 (Ar–C), 133.5 (Ar–C), 159.4 (Ar–C), 159.9
(C]N), 160.0 (C]N), 176.1 (]C–O), 176.5 (]C–O); HRMS: m/z
found [MꢁH]þ 305.1133, C15H17N2O5 requires 305.1137; m/z: 305
(100%, MꢁHþ).
3.4.3. 4-[2-(3-Ethyl-4-nitro-isoxazol-5-yl)-1-hydroxy-propyl]-
benzonitrile 16b
Pale yellow viscous oil, 531 mg, 88%, Rf¼0.2 (CHCl3/MeOH,
98:2), IR (KBr): 3433 br, 2989 w, 2222 s, 1598 s; 1H NMR
(400 MHz, CDCl3): 1.12 (CH–CH3, d, 3H, J¼7.2 Hz), 1.21 (CH2–CH3,
t, 3H, J¼7.2 Hz), 1.25 (CH2–CH3, t, 3H, J¼7.2 Hz), 1.30 (CH–CH3, d,
3H, J¼7.2 Hz), 2.86–2.94 (CH2–CH3, OH, m, 6H), 4.04–4.11 (CH–

M.F.A. Adamo, S. Suresh / Tetrahedron 65 (2009) 990–997
995
3.4.7. 2-(3-Ethyl-4-nitro-isoxazol-5-yl)-1-furan-2-yl-
3.4.11. 3-(3-Ethyl-4-nitro-isoxazol-5-yl)-2-hydroxy-2-phenyl-
propan-1-ol 16f
butyric acid methyl ester epi-16i
Pale yellow viscous oil, 369 mg, 69%, Rf¼0.2 (petroleum ether/
EtOAc, 90:10), IR (KBr): 3430 br, 2993 w, 1595 s; 1H NMR (400 MHz,
CDCl3): 1.15 (CH–CH3, d, 3H, J¼7.2 Hz), 1.21 (CH2–CH3, t, 3H,
J¼7.2 Hz), 1.26 (CH2–CH3, t, 3H, J¼7.2 Hz), 1.41 (CH–CH3, d, 3H,
J¼7.2 Hz), 2.43 (OH, d, 1H, J¼6.4 Hz), 2.52 (OH, d, 1H, J¼5.6 Hz),
2.84–2.96 (CH2–CH3, m, 4H), 4.25–4.29 (CH–CH3, m, 1H), 4.31–4.37
(CH–CH3, m, 1H), 4.91 (CH–OH, dd, 1H, J1¼6.4 Hz, J2¼6.4 Hz), 4.98–
5.01 (CH–OH, m, 1H), 6.14–6.15 (Ar–H, m, 1H), 6.20–6.21 (Ar–H, m,
1H), 6.30 (Ar–H, s, 2H), 7.24–7.25 (Ar–H, m,1H), 7.35–7.36 (Ar–H, m,
1H); 13C NMR (100 MHz, CDCl3): 11.4 (CH2–CH3), 13.1 (CH–CH3),
14.5 (CH–CH3), 19.8 (CH2–CH3), 19.9 (CH2–CH3), 38.7 (CH–CH3), 69.4
(CH–OH), 69.9 (CH–OH), 107.3 (Ar–CH), 108.5 (Ar–CH), 110.3 (Ar–
CH), 110.4 (Ar–CH), 142.6 (Ar–CH), 142.9 (Ar–CH), 153.1 (Ar–C),
153.3 (Ar–C), 159.9 (C]N), 160.1 (C]N), 175.3 (]C–O), 175.7 (]C–
O); HRMS: m/z found [MꢁH]þ 265.0831, C12H13N2O5 requires
265.0824; m/z: 265 (100%, MꢁHþ).
White solid, mp 98–100 ꢀC, 286 mg, 43%, Rf¼0.3 (petroleum
ether/EtOAc, 90:10), IR (KBr): 3477 br, 2955 w, 1741 s, 1586 s; 1H
NMR (400 MHz, CDCl3): 1.17 (CH2–CH3, t, 3H, J¼7.2 Hz), 1.50 (CH–
CH3, d, 3H, J¼6.8 Hz), 2.79 (CH2–CH3, q, 2H, J¼7.6 Hz), 3.96 (CO2CH3,
s, 3H), 5.04 (CH–CH3, q, 1H, J¼7.2 Hz), 7.23–7.28 (m, 3H), 7.51–7.54
(m, 2H); 13C NMR (100 MHz, CDCl3): 11.2 (CH2–CH3), 12.3 (CH–CH3),
19.8 (CH2–CH3), 41.2 (CH–CH3), 53.7 (CO2CH3), 79.6 (C–OH), 125.9
(Ar–CH), 128.5 (Ar–CH), 128.6 (Ar–CH), 128.9 (Ar–CH), 130.1 (Ar–
CH), 138.3 (Ar–C), 159.7 (C]N), 173.6 (]C–O), 174.9 (CO2CH3);
HRMS: m/z found [Mþ] 334.1170, C16H18N2O6 requires 334.1165;
m/z: 334 (100%, Mþ).
3.5. General experimental procedure for the synthesis of
compounds 16j–o (Table 3)
3,5-Diethyl-4-nitroisoxazole 8 (340 mg, 2 mmol) and triethyl-
amine (60 mg, 0.6 mmol) were dissolved in methanol (0.2 mL) and
the contents stirred for 15 min. Then an aliphatic aldehyde
(12 mmol) 15j–o was added to the reaction mixture and this stirred
for 72 h at room temperature. After this time, the solvent was
evaporated and the crude material so obtained purified by flash
column chromatography on silica gel [petroleum ether and ethyl
acetate (95:5)] to give 16j–o.
3.4.8. 4-(3-Ethyl-4-nitro-isoxazol-5-yl)-1-phenyl-pent-
1-en-3-ol 16g
Yellow viscous oil, 273 mg, 45%, Rf¼0.3 (petroleum ether/EtOAc,
80:20), IR (KBr): 3431 br, 3011 w, 2993 w, 1597 s; 1H NMR
(400 MHz, CDCl3): 1.12–1.31 (CH3, m, 9H), 1.35–1.40 (CH3, m, 3H),
1.99 (OH, d, 1H, J¼7.2 Hz), 2.06 (OH, d, 1H, J¼4 Hz), 2.86–2.90 (CH2–
CH3, m, 4H), 3.97–4.00 (CH–CH3, m, 1H), 4.04–4.08 (CH–CH3, m,
1H), 4.49–4.52 (CH–OH, m, 2H), 6.09–6.14 (CHOH–CH]CH, m, 2H),
6.50–6.62 (Ar–CH]CH, m, 2H), 7.18–7.33 (Ar–H, m, 10H); 13C NMR
(100 MHz, CDCl3): 11.2 (CH2–CH3), 12.6 (CH2–CH3), 14.5 (CH–CH3),
19.8 (CH2–CH3), 19.9 (CH2–CH3), 39.3 (CH–CH3), 39.5 (CH–CH3), 74.9
(CH–OH), 75.4 (CH–OH), 126.6 (Ar–CH), 126.7 (Ar–CH), 127.5 (Ar–
CH), 128.0 (Ar–CH), 128.2 (Ar–CH]CH), 128.3 (Ar–CH]CH), 128.6
(Ar–CH), 128.7 (Ar–CH), 128.8 (Ar–CH), 133.0 (Ar–CH]CH), 133.7
(Ar–CH]CH), 135.8 (Ar–C), 135.9 (Ar–C), 160.1 (C]N), 175.8 (]C–
O), 176.1 (]C–O); HRMS: m/z found [MꢁH]þ 301.1180, C16H17N2O4
requires 301.1188; m/z: 301 (100%, MꢁHþ).
3.5.1. 2-(3-Ethyl-4-nitro-isoxazol-5-yl)-4-methyl-pentan-3-ol 16j
Colourless liquid, 86 mg, 18%, Rf¼0.4 (petroleum ether/EtOAc,
90:10), IR (Neat): 3427 br, 2991 w, 1598 s; 1H NMR (400 MHz,
CDCl3): 0.89 (CH3–CH–CH3, d, 3H, J¼6.8 Hz), 0.94 (CH3–CH–CH3, d,
3H, J¼6.8 Hz), 1.25–1.29 (CH2–CH3, CH–CH3, m, 6H), 1.56 (OH, d, 1H,
J¼7.6 Hz), 1.80–1.84 (CH3–CH–CH3, m, 1H), 2.93 (CH2–CH3, q, 2H,
J¼7.6 Hz), 3.65–3.70 (CH–OH, m, 1H), 3.91–3.99 (Is-CH–CH3, m,1H);
13C NMR (100 MHz, CDCl3): 11.2 (CH2–CH3), 14.4 (Is-CH–CH3), 14.9
(CH3–CH–CH3), 20.0 (CH2–CH3), 29.8 (CH3–CH–CH3), 37.2 (Is-CH–
CH3), 78.2 (CH–OH), 159.9 (C]N), 177.3 (]C–O); HRMS: m/z found
[MꢁH]þ 241.1185, C11H17N2O4 requires 241.1188; m/z: 241 (100%,
MꢁHþ).
3.4.9. 3-(3-Ethyl-4-nitro-isoxazol-5-yl)-2-hydroxy-butyric acid
ethyl ester 16h
Pale yellow oil, 283 mg, 52%, Rf¼0.4 (petroleum ether/EtOAc,
80:20), IR (KBr): 3478 br, 2954 w, 1740 s, 1587 s; 1H NMR (400 MHz,
CDCl3): 1.22 (CH2–CH3, t, 3H, J¼7.2 Hz), 1.26–1.34 (CH2–CH3, m, 9H),
1.40 (CH–CH3, d, 3H, J¼6.8 Hz), 1.46 (CH–CH3, d, 3H, J¼7.2 Hz), 2.92–
3.04 (Is-CH2–CH3, m, 4H), 3.27 (OH, d, 1H, J¼7.2 Hz), 3.33 (OH, d, 1H,
J¼5.6 Hz), 4.15–4.28 (CH–CH3, COOCH2–CH3, m, 6H), 4.30–4.34 (CH–
CH3, m, 2H), 4.45–4.50 (CH–OH, m, 1H), 4.58–4.60 (CH–OH, m, 1H);
13C NMR (100 MHz, CDCl3): 11.0 (CH–CH3),11.1 (CH2–CH3),12.6 (CH–
CH3), 13.8 (CH2–CH3), 14.1 (CH2–CH3), 19.8 (Is-CH2–CH3), 37.2 (CH–
CH3), 37.6 (CH–CH3), 62.4 (O–CH2–CH3), 62.7 (O–CH2–CH3), 71.2
(CH–OH), 72.2 (CH–OH), 129.1 (C–NO2),129.8 (C–NO2),160.0 (C]N),
172.4 (]C–O),174.0 (CO2Et),174.8 (CO2Et); HRMS: m/z found [M–H]þ
271.0927, C11H15N2O6 requires 271.0930; m/z: 271 (100%, M–Hþ).
3.5.2. 2-(3-Ethyl-4-nitro-isoxazol-5-yl)-4-methyl-pentan-
3-ol epi-16j
Pale yellow liquid, 316 mg, 65%, Rf¼0.3 (petroleum ether/EtOAc,
90:10), IR (Neat): 3428 br, 2990 w, 1598 s; 1H NMR (400 MHz,
CDCl3): 0.90 (CH3–CH–CH3, d, 3H, J¼6.8 Hz), 0.94 (CH3–CH–CH3, d,
3H, J¼6.8 Hz), 1.27 (CH2–CH3, t, 3H, J¼7.2 Hz), 1.34 (Is-CH–CH3, d,
3H, J¼7.2 Hz), 1.56–1.61 (OH, CH3–CH–CH3, m, 2H), 2.94 (CH2–CH3,
q, 2H, J¼7.2 Hz), 3.62–3.67 (CH–OH, m, 1H), 3.93–4.00 (Is-CH–CH3,
m, 1H); 13C NMR (100 MHz, CDCl3): 11.1 (CH2–CH3), 11.3 (Is-CH–
CH3), 17.6 (CH3–CH–CH3), 19.4 (CH3–CH–CH3), 19.9 (CH2–CH3), 31.5
(CH3–CH–CH3), 36.7 (Is-CH–CH3), 77.7 (CH–OH), 128.6 (C–NO2),
160.1 (C]N), 177.6 (]C–O); HRMS: m/z found [MꢁH]þ 241.1181,
C11H17N2O4 requires 241.1188; m/z: 241 (100%, MꢁHþ).
3.4.10. 3-(3-Ethyl-4-nitro-isoxazol-5-yl)-2-hydroxy-2-phenyl-
butyric acid methyl ester 16i
3.5.3. 2-(3-Ethyl-4-nitro-isoxazol-5-yl)-5-methyl-hexan-3-ol 16k
Pale yellow oil, 123 mg, 24%, Rf¼0.3 (petroleum ether/EtOAc,
90:10), IR (Neat): 3428 br, 2991 w, 1598 s; 1H NMR (400 MHz,
CDCl3): 0.85 (CH3–CH–CH3, d, 3H, J¼6.4 Hz), 0.88 (CH3–CH–CH3, d,
3H, J¼6.8 Hz), 1.25–1.33 (CH2–CH3, Is-CH–CH3, CH2–CH, m, 8H), 1.55
(OH, d, 3H, J¼6.8 Hz), 1.73–1.81 (CH3–CH–CH3, m, 1H), 2.94 (CH2–
CH3, q, 2H, J¼7.6 Hz), 3.79–3.86 (Is-CH–CH3, m, 1H), 3.87–3.93 (CH–
OH, m, 1H); 13C NMR (100 MHz, CDCl3): 11.1 (CH2–CH3), 14.5
(Is-CH–CH3), 19.9 (CH2–CH3), 21.4 (CH3–CH–CH3), 23.8 (CH3–CH–
CH3), 24.4 (CH3–CH–CH3), 40.1 (Is-CH–CH3), 44.1 (CH–CH2), 72.2
(CH–OH), 130.0 (C–NO2), 160.0 (C]N), 176.7 (]C–O); HRMS: m/z
found [MꢁH]þ 255.1341, C12H19N2O4 requires; 255.1345; m/z: 255
(100%, MꢁHþ).
White solid, mp 93–95 ꢀC, 180 mg, 27%, Rf¼0.4 (petroleum
ether/EtOAc, 90:10), IR (KBr): 3477 br, 2954 w, 1741 s, 1586 s; 1H
NMR (400 MHz, CDCl3): 1.24–1.27 (CH2–CH3, m, 3H), 1.35–1.37
(CH–CH3, m, 3H), 3.03 (CH2–CH3, q, 2H, J¼7.2 Hz), 3.66 (CO2CH3, s,
3H), 3.82 (s, OH), 4.78 (CH–CH3, q, 1H, J¼7.2 Hz), 7.38–7.46 (Ar–H,
m, 3H), 7.72–7.74 (Ar–H, m, 2H); 13C NMR (100 MHz, CDCl3): 10.2
(CH2–CH3), 12.5 (CH–CH3), 18.5 (CH2–CH3), 39.7 (CH–CH3), 53.0
(CO2CH3), 79.1 (C–OH),124.0 (Ar–CH),125.5 (Ar–CH),127.3 (Ar–CH),
127.5 (Ar–CH), 128.8 (Ar–CH), 137.9 (Ar–C), 158.4 (C]N), 172.5
(]C–O, CO2CH3); HRMS: m/z found [Mþ] 334.1158, C16H18N2O6
requires 334.1165; m/z: 334 (100%, Mþ).

996
M.F.A. Adamo, S. Suresh / Tetrahedron 65 (2009) 990–997
3.5.4. 2-(3-Ethyl-4-nitro-isoxazol-5-yl)-5-methyl-hexan-
3-ol epi-16k
CH3), 43.2 (CH–CH2–CH3), 75.2 (CH–OH), 160.0 (C]N), 177.5 (]C–
O); HRMS: m/z found [MꢁH]þ 269.1498, C13H21N2O4 requires;
269.1501; m/z: 269 (100%, MꢁHþ).
Pale yellow oil, 317 mg, 62%, Rf¼0.3 (petroleum ether/EtOAc,
90:10), IR (Neat): 3428 br, 2991 w, 1598 s; 1H NMR (400 MHz,
CDCl3): 0.85 (CH3–CH–CH3, d, 3H, J¼6.4 Hz), 0.87 (CH3–CH–CH3, d,
3H, J¼6.8 Hz), 1.28 (CH2–CH3, t, 3H, J¼7.6 Hz), 1.34 (CH–CH3, d, 3H,
J¼7.2 Hz), 1.37–1.43 (CH2–CH, m, 2H), 1.60 (OH, br s, 1H), 1.71–1.76
(CH3–CH–CH3, m, 1H), 2.94 (CH2–CH3, q, 2H, J¼7.6 Hz), 3.80–3.87
(Is-CH–CH3, m, 1H), 4.02–4.04 (CH–OH, m, 1H); 13C NMR (100 MHz,
CDCl3): 11.1 (CH2–CH3), 11.7 (Is-CH–CH3), 19.9 (CH2–CH3), 21.6
(CH3–CH–CH3), 23.5 (CH3–CH–CH3), 24.7 (CH3–CH–CH3), 39.3 (Is-
CH–CH3), 43.5 (CH–CH2–CH), 71.3 (CH–OH), 160.1 (C]N), 176.9
(]C–O); HRMS: m/z found [MꢁH]þ 255.1340, C12H19N2O4 requires;
255.1345; m/z: 255 (100%, MꢁHþ).
3.5.9. 4-Ethyl-2-(3-ethyl-4-nitro-isoxazol-5-yl)-hexan-
3-ol epi-16n
Pale yellow liquid, 214 mg, 39%, Rf¼0.3 (petroleum ether/EtOAc,
90:10), IR (Neat): 3429 br, 2991 w, 1598 s; 1H NMR (400 MHz,
CDCl3): 0.78 (CH2–CH3, t, 3H, J¼7.2 Hz), 0.85 (CH2–CH3, t, 3H,
J¼7.2 Hz), 1.09–1.14 (m, 1H), 1.21–1.23 (m, 1H), 1.27 (CH2–CH3, t, 3H,
J¼7.6 Hz), 1.35–1.39 (m, 4H), 1.45–1.51 (m, 1H), 1.52–1.53 (m, 2H),
2.94 (Is-CH2–CH3, q, 2H, J¼7.2 Hz), 3.87–3.92 (CH–OH, m, 1H),
3.97–4.02 (Is-CH–CH3, m, 1H); 13C NMR (100 MHz, CDCl3): 10.8
(CH2–CH3), 11.0 (CH2–CH3), 11.2 (CH2–CH3), 12.1 (CH–CH3), 19.9
(Is-CH2–CH3), 20.5 (CH–CH2–CH3), 21.8 (CH–CH2–CH3), 36.6 (Is-CH–
CH3), 43.8 (CH–CH2–CH3), 74.0 (CH–OH), 160.0 (C]N), 177.5 (]C–
O); HRMS: m/z found [MꢁH]þ 269.1496, C13H21N2O4 requires;
269.1501; m/z: 269 (100%, MꢁHþ).
3.5.5. 2-(3-Ethyl-4-nitro-isoxazol-5-yl)-nonan-3-ol 16l
Pale yellow oil, 506 mg, 89%, Rf¼0.3 (petroleum ether/EtOAc,
90:10), IR (Neat): 3425 br, 2992 w, 1598 s; 1H NMR (400 MHz,
CDCl3): 0.79–0.83 (m, 3H), 1.18–1.25 (m, 5H), 1.26–1.28 (m, 5H),
1.30–1.32 (m, 3H), 1.39–1.47 (m, 2H), 1.53–1.66 (m, 1H), 1.80–1.82
(OH, m, 1H), 2.93 (CH2–CH3, q, 2H, J¼7.6 Hz), 3.81–3.89 (CH–CH3,
CH–OH, m, 2H); 13C NMR (100 MHz, CDCl3): 11.1 (CH3), 14.1 (CH3),
14.4 (CH3), 19.9 (Is-CH2–CH3), 22.6 (CH2), 25.2 (CH2), 29.1 (CH2),
31.7 (CH2), 34.8 (CH2), 39.6 (CH–CH3), 73.9 (CH–OH), 130.0 (C–NO2),
160.0 (C]N), 176.8 (]C–O); HRMS: m/z found [MꢁH]þ 283.1661,
C14H23N2O4 requires; 283.1658; m/z: 283 (100%, MꢁHþ).
3.5.10. 4-(3-Ethyl-4-nitro-isoxazol-5-yl)-2,2-dimethyl-
pentan-3-ol 16o
Pale brown oil, 78 mg, 15%, Rf¼0.3 (petroleum ether/EtOAc,
90:10), IR (Neat): 3424 br, 2992 w, 1599 s; 1H NMR (400 MHz,
CDCl3): 0.88 ((CH3)3, s, 9H), 1.27 (CH2–CH3, t, 3H, J¼7.2 Hz), 1.42
(CH–CH3, d, 3H, J¼7.2 Hz), 1.80 (OH, d, 1H, J¼6 Hz), 2.93 (CH2–CH3,
q, 2H, J¼7.6 Hz), 3.63–3.66 (CH–OH, m, 1H), 4.01–4.07 (CH–CH3, m,
1H); 13C NMR (100 MHz, CDCl3): 11.2 (CH2–CH3), 13.8 (CH–CH3),
19.9 (CH2–CH3), 26.3 (C–CH3), 35.0 (CH–CH3), 36.2 (C–CH3), 79.1
(CH–OH), 160.1 (C]N), 178.6 (]C–O); HRMS: m/z found [MꢁH]þ
255.1341, C12H19N2O4 requires; 255.1345; m/z: 255 (100%, MꢁHþ).
3.5.6. 1-Cyclohexyl-2-(3-ethyl-4-nitro-isoxazol-5-yl)-
propan-1-ol 16m
Pale yellow oil, 140 mg, 25%, Rf¼0.4 (petroleum ether/EtOAc,
90:10), IR (Neat): 3426 br, 2991 w, 1596 s; 1H NMR (400 MHz,
CDCl3): 1.06–1.09 (m, 1H), 1.12–1.13 (m, 1H), 1.15–1.17 (m, 1H), 1.18–
1.19 (m, 2H), 1.20–1.23 (m, 2H), 1.25 (s, 1H), 1.26–1.27 (m, 3H), 1.28–
1.29 (m, 2H), 1.57–1.58 (m, 1H), 1.61–1.64 (m, 1H), 1.71–1.75 (m, 3H),
2.93 (CH2–CH3, q, 2H, J¼7.6 Hz), 3.62–3.67 (CH–OH, m, 1H), 3.99–
4.02 (CH–CH3, m, 1H); 13C NMR (100 MHz, CDCl3): 11.2 (CH2–CH3),
15.0 (Is-CH–CH3), 19.9 (Is-CH2–CH3), 24.9 (CH2), 25.9 (CH2), 26.3
(CH2), 26.4 (CH2), 30.3 (CH2), 36.4 (Is-CH–CH3), 40.2 (CH2–CH–CH2),
78.1 (CH–OH), 159.9 (C]N), 177.4 (]C–O); HRMS: m/z found
[MꢁH]þ 281.1505, C14H21N2O4 requires; 281.1501; m/z: 281 (100%,
MꢁHþ).
3.5.11. 3-Ethyl-5-(1-methyl-2-phenyl-vinyl)-4-nitroisoxazole 14
Yellow wax, Rf¼0.6 (petroleum ether/EtOAc, 90:10), IR (KBr):
3010 w, 2990 w, 1596; 1H NMR (400 MHz, CDCl3): 1.37 (CH2–CH3, t,
3H, J¼7.6 Hz), 2.31 (]C–CH3, s, 3H), 3.01 (CH2–CH3, q, 2H, J¼7.6 Hz),
7.34 (CH, s, 1H), 7.36–7.37 (Ar–H, m, 1H), 7.41–7.47 (Ar–H, m, 4H);
13C NMR (100 MHz, CDCl3): 11.4 (CH2–CH3), 16.3 (]C–CH3), 20.2
(CH2–CH3), 122.9 (]C–CH), 128.6 (Ar–CH), 128.8 (Ar–CH), 129.7
(Ar–CH), 135.2 (Ar–C), 139.4 (]C–CH), 160.7 (C]N), 171.9 (]C–O);
HRMS: m/z found [Mþ] 258.1010, C61H18N2O6 requires 258.1004;
m/z: 258 (100%, Mþ).
3.5.7. 1-Cyclohexyl-2-(3-ethyl-4-nitro-isoxazol-5-yl)-propan-1-ol
epi-16m
Acknowledgements
Pale yellow oil, 402 mg, 71%, Rf¼0.3 (petroleum ether/EtOAc,
90:10), IR (Neat): 3426 br, 2991 w, 1596 s; 1H NMR (400 MHz,
CDCl3): 0.88–0.98 (m, 1H),1.02–1.09 (m,1H), 1.11 (s, 1H), 1.14 (s, 2H),
1.17–1.20 (m, 1H), 1.24 (CH2–CH3, t, 3H, J¼7.6 Hz), 1.32 (CH–CH3, d,
3H, J¼7.2 Hz), 1.61–1.66 (m, 2H), 1.70–1.76 (m, 3H), 1.83–1.86 (m,
1H), 2.93 (CH2–CH3, q, 2H, J¼7.6 Hz), 3.62–3.66 (CH–OH, m, 1H),
3.95–4.01 (CH–CH3, m, 1H); 13C NMR (100 MHz, CDCl3): 10.4 (CH–
CH3), 11.2 (CH2–CH3), 19.9 (CH2–CH3), 25.8 (CH2), 26.0 (CH2), 26.1
(CH2), 28.4 (CH2), 29.2 (CH2), 36.0 (Is-CH–CH3), 41.0 (CH2–CH–CH2),
77.4 (CH–OH), 128.4 (C–NO2), 160.1 (C]N), 177.9 (]C–O); HRMS:
m/z found [MꢁH]þ 281.1504, C14H21N2O4 requires; 281.1501; m/z:
281 (100%, MꢁHþ).
We would like to acknowledge PTRLI cycle III for a grant to
M.F.A.A. and the Health Research Board (HRB) for financial support
to S.S.
References and notes
1. (a) For reviews, see: Palomo, C.; Oiarbide, M.; Laso, A. Eur. J. Org. Chem. 2007,
2561; (b) Boruwa, J.; Gogoi, N.; Saikia, P. P.; Barua, N. C. Tetrahedron: Asymmetry
2007, 18, 3315; (c) Palomo, C.; Oiarbide, M.; Mielgo, A. Angew. Chem., Int. Ed.
2004, 43, 5442; (d) Luzzio, F. A. Tetrahedron 2001, 57, 915.
2. (a) Arai, T.; Watanabe, M.; Yanagisawa, A. Org. Lett. 2007, 9, 3595; (b) Pfeffer-
korn, J. A.; Choi, C.; Song, Y.; Trivedi, B. K.; Larsen, S. D.; Askew, V.; Dillon, L.;
Hanselman, J. C.; Lin, Z.; Lu, G.; Robertson, A.; Sekerke, C.; Auerbach, B.; Pav-
lovsky, A.; Harris, M. S.; Bainbridge, G.; Caspers, N. Bioorg. Med. Chem. Lett. 2007,
17, 4531; (c) Xiong, Y.; Wang, F.; Huang, X.; Wen, Y.; Feng, X. Chem.dEur. J. 2007,
13, 829; (d) Swiderska, M. A.; Stewart, J. D. Org. Lett. 2006, 8, 6131; (e) Donohoe,
T. J.; Churchill, G. H.; Wheelhouse, K. M. P.; Glossop, P. A. Angew. Chem., Int. Ed.
2006, 45, 8025; (f) Ballini, R.; Barboni, L.; Fiorini, D.; Giarlo, G.; Palmieri, A.
Green Chem. 2005, 7, 828.
3. (a) Chung, W. K.; Chiu, P. Synlett 2005, 55; (b) El Blidi, L.; Crestia, D.; Gallienne,
E.; Demuynck, C.; Bolte, J.; Lemaire, M. Tetrahedron: Asymmetry 2004, 15, 2951;
(c) Soengas, R. G.; Estevez, J. C.; Estevez, R. J. Org. Lett. 2003, 5, 4457; (d) Smith,
P. W.; Trivedi, N.; Howes, P. D.; Sollis, S. L.; Rahim, G.; Bethell, R. C.; Lynn, S.
Bioorg. Med. Chem. Lett. 1999, 9, 611; (e) McNulty, J.; Mo, R. Chem. Commun.
1998, 933; (f) Chou, W.-C.; Fotsch, C.; Wong, C.-H. J. Org. Chem. 1995, 60, 2916;
(g) Yoshikawa, M.; Murakami, N.; Yokokawa, Y.; Inoue, Y.; Kuroda, Y.; Kitagawa,
I. Tetrahedron 1994, 50, 9619.
3.5.8. 4-Ethyl-2-(3-ethyl-4-nitro-isoxazol-5-yl)-hexan-3-ol 16n
Pale yellow liquid, 36 mg, 7%, Rf¼0.3 (petroleum ether/EtOAc,
90:10), IR (Neat): 3428 br, 2990 w, 1598 s; 1H NMR (400 MHz,
CDCl3): 0.87 (CH2–CH3, t, 3H, J¼7.2 Hz), 0.92 (CH2–CH3, t, 3H,
J¼7.2 Hz), 1.18–1.23 (m, 3H), 1.25–1.29 (m, 7H), 1.45–1.50 (m, 2H),
2.93 (Is-CH2–CH3, q, 2H, J¼7.6 Hz), 3.86–3.91 (CH–OH, m, 1H),
4.00–4.08 (Is-CH–CH3, m, 1H); 13C NMR (100 MHz, CDCl3): 11.2
(CH2–CH3), 11.7 (CH2–CH3), 12.1 (CH2–CH3), 14.9 (CH–CH3), 19.7
(CH–CH2–CH3), 19.9 (Is-CH2–CH3), 22.6 (CH–CH2–CH3), 36.9 (Is-CH–

M.F.A. Adamo, S. Suresh / Tetrahedron 65 (2009) 990–997
997
4. (a) For review, see: Westermann, B. Angew. Chem., Int. Ed. 2003, 42, 151; (b) Li,
11. Adamo, M. F. A.; Duffy, E. F. Org. Lett. 2006, 8, 5157.
12. Adamo, M. F. A.; Konda, V. R. Org. Lett. 2007, 9, 303.
13. Adamo, M. F. A.; Duffy, E. F.; Donati, D.; Sarti-Fantoni, P. Tetrahedron 2007,
63, 2047.
14. Adamo, M. F. A.; Duffy, E. F.; Donati, D.; Sarti-Fantoni, P. Tetrahedron 2007,
63, 2684.
15. Adamo, M. F. A.; Konda, V. R.; Donati, D.; Sarti-Fantoni, P.; Torroba, T. Tetrahe-
dron 2007, 63, 9741.
16. (a) Cortes, C. E.; Cortes, R. E.; Martinez, R.; Avila, G.; Sandoval, A. J. Heterocycl.
Chem. 1989, 26, 1561; (b) Chimichi, S.; De Sio, F.; Donati, D.; Pepino, R.; Rabatti,
L.; Sarti-Fantoni, P. J. Heterocycl. Chem. 1983, 20, 105; (c) Chimichi, S.; De Sio, F.;
Donati, D.; Fina, G.; Pepino, R.; Sarti-Fantoni, P. Heterocycles 1983, 20, 263.
17. A modified procedure was used for the preparation of 3,5-diethyl-4-nitro-
isoxazole considering the reported procedure for the preparation of 3,5-di-
methyl-4-nitroisoxazole. See: Pe´rez, J. D.; Wunderlin, D. A. J. Org. Chem. 1987,
52, 3637.
18. (a) Pellissier, H. Tetrahedron 2007, 63, 9267; (b) Shi, M.; Lei, Z.-Y.; Zhao, M.-X.;
Shi, J.-W. Tetrahedron Lett. 2007, 48, 5743; (c) Li, H.; Wang, B.; Deng, L. J. Am.
Chem. Soc. 2006, 128, 732; (d) Wang, J.; Li, H.; Zu, L.; Wang, W. Org. Lett. 2006, 7,
1391; (e) Nakadai, M.; Saito, S.; Yamamoto, H. Tetrahedron 2002, 58, 8167; (f)
Marcelli, M.; van der Haas, R. N. S.; vanMaarseveen, J.; Hiemstra, H. Synlett
2005, 2817.
Z.; Bohle, D. S.; Li, C.-J. Proc. Natl. Acad. Sci. U.S.A. 2006, 103, 8928; (c) Palomo, C.;
Vera, S.; Mielgo, A.; Go´mez-Bengoa, E. Angew. Chem., Int. Ed. 2006, 45, 5984; (d)
Bernardi, L.; Fini, F.; Herrera, R. P.; Ricci, A.; Sgarzani, V. Tetrahedron 2006, 62,
375; (e) Kotti, S. R. S. S.; Timmons, C.; Li, G. Chem. Biol. Drug Des. 2006, 67, 101;
(f) Palomo, C.; Oiarbide, M.; Arceo, E.; Garcı´a, J. M.; Lo´pez, R.; Gonza´lez, A.;
Linden, A. Angew. Chem., Int. Ed. 2005, 44, 6187; (g) Anderson, J. C.; Howell, G.
P.; Lawrence, R. M.; Wilson, C. S. J. Org. Chem. 2005, 70, 5665; (h) Palomo, C.;
Oiarbide, M.; Laso, A. Angew. Chem., Int. Ed. 2005, 44, 3881; (i) Ruano, J. L. G.;
ˇ ´
Topp, M.; Lo´pez-Cantarero, J.; Alema´n, J.; Remuinan, M. J.; Cid, M. B. Org. Lett.
2005, 7, 4407; (j) Nugent, B. M.; Yoder, R. A.; Johnston, J. N. J. Am. Chem. Soc.
2004, 126, 3418.
5. Murata, S.; Tsubone, Y.; Kawai, R.; Eguchi, D.; Tomioka, H. J. Phys. Org. Chem.
2005, 18, 9.
6. Rollins, S. B.; Williams, R. M. Tetrahedron Lett. 1997, 38, 4033.
7. Williams, R. M.; Rollins, S. B.; Judd, T. C. Tetrahedron 2000, 56, 521.
8. Judd, T. C.; Williams, R. M. Org. Lett. 2002, 4, 3711.
9. Adamo, M. F. A.; Duffy, E. F.; Konda, V. R.; Murphy, F. Heterocycles 2007, 71, 1173
and references cited therein.
10. (a) Adamo, M. F. A.; Chimichi, S.; De Sio, F.; Donati, D.; Sarti-Fantoni, P. Tetra-
hedron Lett. 2002, 43, 4157; (b) Adamo, M. F. A.; Donati, D.; Duffy, E. F.; Sarti-
Fantoni, P. J. Org. Chem. 2005, 70, 8395.