Stable nitrile oxide dipolar cycloadditions in pure water

Article abstract of DOI:10.1016/j.tet.2011.07.037

A systematic study on the behaviour of stable 2,4,6-trimethyl-3,5- dichlorobenzonitrile oxide versus a number of mono-, bi- and trisubstituted dipolarophiles in water was pursued obtaining simple as well as annulated isoxazolines. Reaction conditions chan

Full text of DOI:10.1016/j.tet.2011.07.037

Tetrahedron 67 (2011) 7343e7347
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Stable nitrile oxide dipolar cycloadditions in pure water
*
Giorgio Molteni , Paola Del Buttero
ꢀ
Universita degli Studi di Milano, Dipartimento di Chimica Organica e Industriale, via Golgi 19, 20133 Milano, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 11 May 2011
Received in revised form 22 June 2011
Accepted 12 July 2011
Available online 21 July 2011
A systematic study on the behaviour of stable 2,4,6-trimethyl-3,5-dichlorobenzonitrile oxide versus
a number of mono-, bi- and trisubstituted dipolarophiles in water was pursued obtaining simple as well
as annulated isoxazolines. Reaction conditions changed with the dipolarophilic species, according to
their solubility in water and the degree of substitution of the reactive carbonecarbon multiple bond. The
presence of sodium dodecylsulfate was also tested as potential micellar catalyst.
Ó 2011 Elsevier Ltd. All rights reserved.
1. Introduction
work we undertook a systematic investigation on the behaviour of
the stable 2,4,6-trimethyl-3,5-dichlorobenzonitrile oxide onto
During the last two decades, 1,3-dipolar cycloadditions (1,3-DC)
in water or aqueous media have been recognized as an useful, non-
conventional method with wide application in the synthesis of
a huge number of five-membered heterocyclic rings.1 This is pri-
marily due to the straightforward features of water as the reaction
medium. In fact, despite the aggressive nature of water towards
a number of organic functionalities, water itself displays a number
of desirable features: (i) the pH of the reaction medium is often
easily controlled, (ii) reaction rates can be dramatically increased
by means of the hydrophobic effect, (iii) product separation
and/or reaction workup is generally greatly simplified and (iv)
environmentally-friendly procedures can be successfully elabo-
rated. Early contributions by Grundmann described nitrile oxide
cycloadditions in biphasic aqueouseorganic mixtures.2 Later, fur-
ther examples of dipolar cycloadditions in water or aqueous media
have been exploited,3 leading to some successful synthetic meth-
odologies (the well-known ‘click’ azideealkyne cycloaddition).4 By
focussing on the field of nitrile oxide chemistry,5 some papers have
appeared in recent years describing the 1,3-dipolar activity of such
species in aqueous systems from both a mechanistic6 and syn-
thetic7 standpoint. To date, however, no systematic studies of stable
nitrile oxide 1,3-DC in pure water have been performed. In fact,
nitrile oxides are almost always generated in situ from the whole
array of their precursors,5 which are usually fully insoluble in water.
As a result, an organic cosolvent is very often required giving rise to
a variety of experimental conditions spanning from homogeneous8
to biphasic systems.9 We argued that a thermally stable nitrile
oxide could tolerate the use of pure water as the reaction medium
thus circumventing the use of organic solvent. Hence, in the present
a variety of alkenyl-, alkynyl- and hetero- dipolarophiles in water.
2. Results and discussion
As a suitable dipolar species, nitrile oxide 1 (Scheme 1) was
prepared according to literature procedures.10 This nitrile oxide was
submitted to reaction with a number of dipolarophilic species in
pure water at room temperature as summarised in Schemes 1e4
and Tables 1e3. The results were satisfactory, provided that very
short reaction times and mild conditions were in place with respect
to some reactions carried out in organic solvent as control experi-
ments (vide infra, note 14), and very good isolation yields were
always experienced. Furthermore, reaction workup was a very
simple matter since the crude product was collected by filtration,
thus avoiding any chromatographic separation. Further
+
_
Ar
N
O
1
R
water, rt
Ar
N OH
Ar
HN
N
R
O
2
3
Me
Me
Cl
Cl
Ar =
Me
a: R = CO2Et, b: R = CN, c: R = CH2Br, d: R = OEt,
e: R = Ph, f: R = CH2OH, g: R = NH2
* Corresponding author. Tel.: þ39 02 50314141; fax: þ39 02 50314139; e-mail
Scheme 1.
address: giorgio.molteni@unimi.it (G. Molteni).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.07.037

7344
G. Molteni, P. Del Buttero / Tetrahedron 67 (2011) 7343e7347
Table 2
crystallisation gave analytically pure products 2e13 whose struc-
tures were established unambiguously on the basis of spectro-
scopic as well as spectrometric data.
Cycloaddition between nitrile oxide 1 and monosubstituted acetylenes in watera
Entry
R1
Catalyst
Time (h)
Products and yields (%)b
4
5
SDSc
__
SDS
__
SDS
__
SDS
__
1.5
1.5
2.5
2.5
2.5
3
4
4
2.5
4
4
88
83
63
72
71
78
0
0
83
0
__
__
__
__
__
__
__
__
__
__
__
87
Ar
1
2
3
4
5
6
7
8
CO2Me
CO2Me
CH2Cl
CH2Cl
Ph
N
R1
O
4
R1
Ph
CH2OH
CH2OH
CH2OH
CH2NH2
CH2NH2
CH2NH2
1
water, rt
9d
10
11
12d
__
SDS
__
Ar
N OH
HN
0
__
__
2.5
a
At room temperature.
Isolated product yield after crystallisation with diisopropyl ether.
Sodium dodecylsulfate.
5
b
c
a: R1 = CO2Me, b: R1 = CH2Cl, c: R1 = Ph, d: R1 = CH2OH, e: R1 = CH2NH2
d
In 4.0 M aqueous sodium chloride.
Scheme 2.
Table 3
Cycloaddition between nitrile oxide 1 and bi- or trisubstituted ethylenes in boiling
water
Ar
N
Entry
Ethylene
Product
Time (h)
Product yield (%)a
N
CO2Et
water, rt
1
1
2
3
4
5
6
7
cis-Stilbene
trans-Stilbene
7
8
9
10
11
12b
13b
2
2.5
3
2
2
88
84
76
67
85
89
91
N
CO2Et
O
Dimethylfumarate
1,4,5,6-Tetrahydropyran
Norbornene
(S)-cis-Verbenol
(1S)-(ꢀ)-Verbenone
6 (84%)
Scheme 3.
3.5
3
a
Isolated product yield after crystallisation with diisopropyl ether.
H
H
Ar
Ph
Ar
Ph
Ar
CO2Me
Ar
Ar
O
H
Enantiomeric excess was >95:5 as determined by 1H NMR in the presence of tris
b
[heptafluoropropyl-hydroxymethylene-(þ)-camphorato]europium-(III).
N
N
N
N
N
Ph
Ph
CO2Me
O
O
O
O
O
H
11
7
8
9
10
As far as monosubstituted ethylenic dipolarophiles were con-
cerned (Scheme 1, Table 1) several issues deserve to be highlighted.
First, it can be noted that the extent of cycloaddition is satisfactory
provided that the mentioned dipolarophilic counterparts are liquids,
which are insoluble or sparingly soluble in water. This finding is
substantiated by the fact that no reaction occurred in the presence of
water-soluble dipolarophiles like allyl alcohol (Table 1, entries 11, 12)
and allylamine (Table 1, entries 14, 15) since in these latter two cases
unreacted 1 was recovered. It is likely that nitrile oxide cycloadditions
in water take place due to the hydrophobic effect.11 A fully soluble
reactant (dipolarophile) cannot be forced in a close space with 1 and
by consequence a fruitful reaction is ruled out. To circumvent this
solubility problem, we reasoned that aqueous solutions of salts,
which enhance the ionic strength of the reaction medium would be
able to squeeze out the (dipolarophilic) organic liquid thus allowing
reaction with 1. Thus, both reactions with allyl alcohol and allylamine
were repeated in 4 M aqueous sodium chloride at room temperature.
While allyl alcohol behaves as a good dipolarophile in these condi-
tions giving thedesired isoxazoline in 88% yield(Table 1, entry 13), the
marked nucleophilic character of allylamine precluded the formation
of the corresponding cycloadduct, instead giving the open-chain
product 3 (Table 1, entry 16). As a further remark concerning the
present nitrile oxide cycloadditions with monosubstituted ethylenes,
the regioselectivity issue occupies a prominent place. It can be noted
that only the 5-substituted isoxazolines 2 were formed from these
reactions. This general behaviour is expected on the basis of the
predicted energies and shapes of the FMO’s involved in the cycload-
ditions.12 It can be that in the case of electron-rich dipolarophiles the
LUMO-dipole controlled process, which works in vacuo (e.g., within
solvents with a low dielectric constant) may be reinforced in water
due to the lesser hydrogen-bonding stabilisation of dipolarophiles
FMO’s with respect to that of the nitrile oxide.13 With electron-poor
dipolarophiles, the known nitrile oxide-HOMO control12 should
HO
O
H
H
Ar
Ar
N
N
O
O
12
13
Scheme 4.
Table 1
Cycloaddition between nitrile oxide 1 and monosubstituted ethylenes in watera
Entry
R
Catalyst
Time (h)
Products and yields (%)b
2
3
1
2
3
4
5
6
7
8
CO2Et
CO2Et
CN
SDSc
__
2
2
2
2.5
2.5
3
3
4
3
3
4
4
3
4
4
3
84
81
85
84
69
76
77
81
76
78
0
0
88
0
0
0
__
__
__
__
__
__
__
__
__
__
__
__
__
__
__
90
SDS
__
SDS
__
SDS
__
SDS
__
SDS
__
__
SDS
__
__
CN
CH2Br
CH2Br
OEt
OEt
Ph
9
10
11
12
13d
14
15
16d
Ph
CH2OH
CH2OH
CH2OH
CH2NH2
CH2NH2
CH2NH2
a
At room temperature.
Isolated product yield after crystallisation with diisopropyl ether.
Sodium dodecylsulfate.
b
c
d
In 4.0 M aqueous sodium chloride.

G. Molteni, P. Del Buttero / Tetrahedron 67 (2011) 7343e7347
7345
also work in water due to the comparable stabilisation of both re-
actants FMO’s.13 In fact, we observed short reaction times irrespective
of the electronic features of the dipolarophile. In some control ex-
periments, ethyl acrylate and ethylvinyl ether were submitted to re-
simple as well as annulated isoxazolines. Water insoluble or spar-
ingly soluble monosubstituted dipolarophiles react smoothly with
1 at room temperature, while the reactivity of water-soluble spe-
cies is spurred by the presence of sodium chloride as an enhancer of
the reaction medium ionic strength. The presence of SDS as a sur-
factant in the reaction mixture did not reduce significantly the
reaction times. Isoxazolines 7e9 confirm the concerted nature of
nitrile oxide cycloadditions in water, while enantiopure products
12 and 13 were obtained through complete diastereofacial-
selective cycloadditions.
action with
1 in boiling carbon tetrachloride obtaining the
corresponding cycloadducts 2a and 2d after 7 h.14
Due to the ability of some surfactants to speed-up 1,3-DC in
water,15,16 all the above reactions involving monosubstituted
alkenyl dipolarophiles were also performed in the presence of so-
dium dodecylsulfate (SDS). By setting the SDS concentration as
15 mM, the formation of micelles can be expected, provided that
the critical micellar concentration (CMC) of SDS is known to be
8.2 mM in water.15 Close inspection of the reaction times reported
in Table 1 reveal that a mechanistic picture involving some kind of
micellar catalysis can be ruled out, i.e., the presence of SDS did not
enhance significantly reaction times.
All the above considerations may be roughly applied to mono-
substituted acetylenic dipolarophiles as can be inferred from both
Scheme 2 and Table 2.
In order to complete the picture concerning the reactivity of 1
towards monosubstituted dipolarophiles, our attention was turned
to ethylcyanoformate as a valuable heterodipolarophile (Scheme 3).
After 2 h at room temperature the expected 1,2,4-oxadiazole 6 was
obtained in 84% yield.
The results described and discussed up to this point show the
ease of reaction between 1 and monosubstituted dipolarophiles.
However, when attempting the reaction between 1 and norbornene
under the same conditions, unchanged reactants were recovered. It
could be likely that enthalpic factors are responsible for this disap-
pointing outcome. Thus, we decided to submit bi- and trisubstituted
ethylenes to reaction with 1 in boiling water. As can be seen from
Table 3, isolation yields of products 7e13 (Scheme 4) were quite
satisfactory in these latter conditions. The obtainment of isoxazo-
lines 7e9 as single diastereoisomers is particularly significant since
it points out the concerted nature of nitrile oxide 1,3-DC inwater, i.e.,
the stereochemistry of the corresponding 1,2-disubstituted ethyl-
enes is retained through the 1,3-DC’s (Table 3, entries 1e3).
As a further step of the present work, two naturally-occurring
oxygenated monoterpenes of the pinane family, namely (S)-cis-
verbenol and (1S)-(ꢀ)-verbenone, were reacted with 1 giving
cycloadducts 12 and 13, respectively, as single diastereoisomers in
the enantiopure form (Table 3, entries 6, 7 and Table 3, footnote b).
Structures 12 and 13 were assigned on the basis of NOESY experi-
ments having observed NOE enhancement between H and HAꢀC as
depicted in Fig. 1, in the same way to that previously found onto
similar annulated pyrazoles.17
4. Experimental section
4.1. General
€
Melting points were determined on a Buchi apparatus in open
tubes and are uncorrected. IR spectra were recorded on a Per-
kineElmer 1725 X spectrophotometer. Mass spectra were de-
termined on a VG-70EQ apparatus. 1H NMR (300 MHz) and 13C
NMR (75 MHz) spectra were taken with a Bruker AMX 300 in-
strument (in CDCl3 solutions at room temperature). Chemical shifts
are given as parts per million from tetramethylsilane. Coupling
constants (J) values are given in hertz and are quoted to ꢁ0.1 Hz
consistently with NMR machine accuracy. NOESY experiments
were performed by setting the following parameters: relaxation
delay (d1) 2 s, irradiation power (dl2) 74 dB and total irradiation
time (for each signal) 1.8 s. Optical rotations were recorded on
a PerkineElmer 241 polarimeter at the sodium D-line at 25 ꢂC.
4.2. Reaction between nitrile oxide 1 and monosubstituted
dipolarophiles in water: general procedure
A mixture of 1 (0.12 g, 0.52 mmol) and the appropriate mono-
substituted dipolarophile (0.78 mmol) in water (3.5 mL) was
mechanically shaken at room temperature for the time indicated in
Tables 1 and 2. The resulting mixture was filtered, the solid material
was washed with water (5 mL) and dried in vacuo. Further crys-
tallisation with diisopropyl ether gave pure 2, 4 or 6.
4.2.1. 3-(2,4,6-Trimethyl-3,5-dichloro)phenyl-5-ethoxycarbonyl-4,5-
dihydroisoxazole 2a. White powder, mp 135e137 ꢂC; 1H NMR
(300 MHz, CDCl3):
3.38e3.43 (2H, m), 4.30 (2H, q, J¼7.1), 5.17 ppm (1H, dd, J¼7.7, 2.0);
13C NMR (75 MHz, CDCl3):
¼16.7 (q),18.0 (q), 20.2 (q), 44.1 (t), 46.6
d¼1.35 (3H, t, J¼7.1), 2.29 (6H, s), 2.53 (3H, s),
d
(t), 85.9 (d), 126.0 (s), 130.6 (s), 133.7 (s), 136.2 (s), 156.5 (s),
167.1 ppm (s); IR (Nujol):
mental analysis calcd (%) for C15H17Cl2NO3: C 54.56, H 5.19, N 4.24;
found: C 54.60, H 5.22, N 4.29.
n
¼1740 cmꢀ1; MS: m/z: 329 [Mþ]; ele-
9.6%
OH
12.8%
O
HA
HA
H
H
Ar
Ar
4.2.2. 3-(2,4,6-Trimethyl-3,5-dichloro)phenyl-5-cyano-4,5-
dihydroisoxazole 2b. White powder, mp 110e113 ꢂC; 1H NMR
HB
HC
HB
HC
N
N
(300 MHz, CDCl3):
d
¼2.37 (6H, s), 2.55 (3H, s), 3.42 (1H, dd, J¼11.6,
O
O
3.3), 3.58 (1H, dd, J¼11.6, 7.2), 5.42 ppm (1H, dd, J¼7.2, 3.3); 13C
12
13
NMR (75 MHz, CDCl3):
d
¼18.2 (q), 19.8 (q), 44.0 (t), 72.4 (d), 127.2
(s), 133.6 (s), 134.4. (s), 137.8 (s), 156.6 (s), 176.9 ppm (s); IR (Nujol):
Fig. 1. NOE enhancements for products 12 and 13.
n
¼2250 cmꢀ1; MS: m/z: 282 [Mþ]; elemental analysis calcd (%) for
In these latter two cases, the severe steric hindrance exerted
by the two methyl groups placed onto the cyclobutyl ring of
the dipolarophiles is responsible for the observed complete
stereoselectivity.
C13H12Cl2N2O: C 55.14, H 4.27, N 9.89; found: C 55.18, H 4.30, N 9.92.
4.2.3. 3-(2,4,6-Trimethyl-3,5-dichloro)phenyl-5-bromomethyl-4,5-
dihydroisoxazole 2c. Pale yellow powder, mp 128e130 ꢂC; 1H NMR
(300 MHz, CDCl3):
d
¼2.32 (6H, s), 2.54 (3H, s), 3.13 (1H, dd, J¼17.9,
3. Conclusions
7.4), 3.26 (1H, dd, J¼17.9, 10.4), 3.58 (1H, dd, J¼10.5, 7.5), 3.65 (1H,
dd, J¼10.5, 4.1), 4.95e5.10 ppm (1H, m); 13C NMR (75 MHz, CDCl3):
The reactivity of stable nitrile oxide 1 towards a number of
dipolarophiles has been exploited in pure water giving an array of
d
¼17.7 (q), 18.4 (q), 32.6 (t), 43.2 (t), 78.7 (d), 127.9 (s), 132.6 (s),
133.2 (s), 135.2 (s), 156.0 ppm (s); IR (Nujol):
n
¼680 cmꢀ1; MS: m/z:

7346
G. Molteni, P. Del Buttero / Tetrahedron 67 (2011) 7343e7347
350 [Mþ]; elemental analysis calcd (%) for C13H14BrCl2NO: C 44.48,
H 4.02, N 3.99; found: C 44.52, H 3.98, N 4.04.
in Tables 1 and 2. The mixture was extracted with dichloro-
methane (2ꢃ10 mL), the organic layer was washed with water
(3ꢃ10 mL) and dried over sodium sulfate. Evaporation at reduced
pressure gave a residue, which was crystallised with diisopropyl
ether giving pure 2, 4 or 6.
4.2.4. 3-(2,4,6-Trimethyl-3,5-dichloro)phenyl-5-ethoxy-4,5-
dihydroisoxazole 2d. White powder, mp 106e109 ꢂC; 1H NMR
(300 MHz, CDCl3):
d
¼1.29 (3H, t, J¼7.1), 2.32 (6H, s), 2.57 (3H, s), 2.95
(1H, dd, J¼17.8, 1.2), 3.26 (1H, dd, J¼17.8, 6.3), 3.68 (1H, dq, J¼14.2,
4.4. Reaction between nitrile oxide 1 and monosubstituted
dipolarophiles in aqueous 4 M sodium chloride: general
procedure
7.0), 3.98 (1H, dq, J¼14.2, 7.2), 5.70 ppm (1H, dd, J¼6.3,1.2); 13C NMR
(75 MHz, CDCl3):
d
¼15.02 (q),18.0 (q),18.9 (q), 45.9 (t), 63.7 (t),102.4
(d), 128.8 (s), 133.3 (s), 133.5 (s), 135.5 (s), 157.7 ppm (s); IR (Nujol):
n
¼1140 cmꢀ1; MS: m/z: 301 [Mþ]; elemental analysis calcd (%) for
A mixture of 1 (0.12 g, 0.52 mmol), the appropriate mono-
substituted dipolarophile (0.78 mmol) in 4 M aqueous sodium
chloride (3.5 mL) was mechanically shaken at room temperature
for the time indicated in Table 1, entries 13,16 and Table 2, entries 9,
12. The resulting mixture was filtered, the solid material was
washed with water (2ꢃ5 mL) and dried in vacuo. Further crystal-
lisation with diisopropyl ether gave pure 2e5.
C14H17Cl2NO2: C 55.64, H 5.67, N 4.63; found: C 55.60, H 5.70, N 4.67.
4.2.5. 3-(2,4,6-Trimethyl-3,5-dichloro)phenyl-5-phenyl-4,5-
dihydroisoxazole 2e. Pale yellow powder, mp 91e92 ꢂC; 1H NMR
(300 MHz, CDCl3):
8.3), 3.56 (1H, dd, J¼17.4, 10.9), 5.82 (1H, dd, J¼10.9, 8.3),
7.34e7.43 ppm (5H, m); 13C NMR (75 MHz, CDCl3):
¼18.1 (q), 18.9
(q), 47.6 (t), 82.1 (d), 125.6 (d), 128.3 (d), 128.8 (d), 133.2 (s), 133.6
d¼2.28 (6H, s), 2.56 (3H, s), 3.09 (1H, dd, J¼17.4,
d
4.4.1. 3-(2,4,6-Trimethyl-3,5-dichloro)phenyl-5-hydroxymethyl-4,5-
(s), 135.5 (s), 140.7 (s), 156.5 ppm (s); IR (Nujol):
n
¼1950,
dihydroisoxazole 2f. White powder, mp 120e121 ꢂC; 1H NMR
1880 cmꢀ1; MS: m/z: 333 [Mþ]; elemental analysis calcd (%) for
(300 MHz, CDCl3):
d
¼2.08e2.20 (1H, br s), 2.29 (6H, s), 2.53 (3H, s),
C18H17Cl2NO: C 64.68, H 5.13, N 4.19; found: C 64.71, H 5.11, N 4.22.
3.08 (1H, dd, J¼17.8, 9.3), 3.17 (1H, dd, J¼17.8, 11.1), 3.68 (1H, dd,
J¼12.3, 3.8), 3.95 (1H, dd, J¼12.3, 2.9), 4.85e4.98 ppm (1H, m); 13C
4.2.6. 3-(2,4,6-Trimethyl-3,5-dichloro)phenyl-5-methoxycarbony-
NMR (75 MHz, CDCl3):
d¼18.3 (q),18.8 (q), 43.6 (t), 48.8 (t), 75.2 (d),
lisoxazole 4a. White powder, mp 111e112 ꢂC; 1H NMR (300 MHz,
127.7 (s), 132.9 (s), 133.7 (s), 134.1 (s), 156.8 ppm (s); IR (Nujol):
CDCl3):
d
¼2.16 (6H, s), 2.55 (3H, s), 4.02 (3H, s), 6.87 ppm (1H, s);
n
¼3420 cmꢀ1; MS: m/z: 287 [Mþ]; elemental analysis calcd (%) for
13C NMR (75 MHz, CDCl3):
d
¼18.3 (q), 18.8 (q), 43.8 (q), 107.8 (d),
C13H15Cl2NO2: C 54.18, H 5.25, N 4.86; found: C 54.22, H 5.22, N
4.90.
127.6 (s), 128.7 (s), 133.2 (s), 133.8 (s), 134.1 (s), 162.1 (s), 168.0 ppm
(s); IR (Nujol):
calcd (%) for C14H13Cl2NO3: C 53.52, H 4.17, N 4.46; found: C 53.57, H
4.20, N 4.49.
n
¼1730 cmꢀ1; MS: m/z: 313 [Mþ]; elemental analysis
4.4.2. 3-(2,4,6-Trimethyl-3,5-dichloro)phenyl-5-hydroxymethyli-
soxazole 4d. White powder, mp 97e99 ꢂC; 1H NMR (300 MHz,
CDCl3):
d
¼2.2e2.30 (1H, br s, overlapping), 2.25 (6H, s), 2.57 (3H, s),
4.2.7. 3-(2,4,6-Trimethyl-3,5-dichloro)phenyl-5-chloromethyliso-
3.14 (1H, d, J¼17.6), 3.23 (1H, d, J¼17.6), 6.51 ppm (1H, s); 13C NMR
xazole 4b. White powder, mp 76e78 ꢂC; 1H NMR (300 MHz, CDCl3):
(75 MHz, CDCl3):
d
¼18.1 (q), 19.2 (q), 43.8 (t), 106.5 (d), 127.7 (s),
d
¼2.16 (6H, s), 2.55 (3H, s), 4.69 (2H, s), 6.25 ppm (1H, s); 13C NMR
133.0 (s), 133.7 (s), 135.6 (s), 158.8 (s), 163.4 ppm (s); IR (Nujol):
(75 MHz, CDCl3):
d
¼18.7 (q),19.1 (q), 34.4 (t),105.0 (d),128.4 (s),133.6
n
¼3410 cmꢀ1; MS: m/z: 285 [Mþ]; elemental analysis calcd (%) for
(s), 133.9 (s), 135.8 (s), 162.3 (s), 168.3 ppm (s); IR (Nujol):
C13H13Cl2NO2: C 54.57, H 4.58, N 4.89; found: C 54.60, H 4.60, N
4.93.
n
¼775 cmꢀ1; MS: m/z: 303 [Mþ]; elemental analysis calcd (%) for
C13H12Cl3NO: C 51.26, H 3.97, N 4.60; found: C 51.23, H 4.00, N 4.56.
4.4.3. 1-Allylamino-(2,4,6-trimethyl-3,5-dichloro)benzaldehyde ox-
4.2.8. 3-(2,4,6-Trimethyl-3,5-dichloro)phenyl-5-phenylisoxazole
ime 3. Yellow powder, mp 57e59 ꢂC; 1H NMR (300 MHz, CDCl3/
4c. Pale yellow powder, mp 104e105 ꢂC; 1H NMR (300 MHz,
D2O):
d
¼2.31 (6H, s), 2.52 (3H, s), 3.30e3.40 (2H, m), 5.00e5.13 (2H,
CDCl3):
d
¼2.23 (6H, s), 2.58 (3H, s), 6.44 (1H, s), 7.48e7.83 ppm (5H,
m), 5.54e5.72 ppm (1H, m); IR (Nujol):
n
¼3520, 3375 cmꢀ1; MS: m/
m); 13C NMR (75 MHz, CDCl3):
d
¼18.5 (q), 18.8 (q), 107.7 (d), 123.9
z: 286 [Mþ]; elemental analysis calcd (%) for C13H16Cl2N2O: C 54.37,
(d), 125.2 (d), 128.2 (d), 128.7 (s), 132.6 (s), 133.4 (s), 133.7 (s), 137.8
H 5.62, N 9.75; found: C 54.41, H 5.59, N 9.71.
(s),156.2 (s),163.7 ppm (s); IR (Nujol):
n
¼1970,1840 cmꢀ1; MS: m/z:
331 [Mþ]; elemental analysis calcd (%) for C18H15Cl2NO: C 65.08, H
4.55, N 4.22; found: C 65.11, H 4.52, N 4.27.
4.4.4. 1-Propargylamino-(2,4,6-trimethyl-3,5-dichloro)benzaldehyde
oxime 5. Yellow powder, mp 66e67 ꢂC; 1H NMR (300 MHz, CDCl3/
D2O):
d
¼1.27 (1H, t, J¼1.4), 2.27 (6H, s), 2.54 (3H, s), 3.42 ppm (2H,
4.2.9. 3-(2,4,6-Trimethyl-3,5-dichloro)phenyl-5-ethoxycarbonyl-
d, J¼1.5); IR (Nujol):
n
¼3535, 3355 cmꢀ1; MS: m/z: 284 [Mþ]; ele-
1,2,4-oxadiazole 6. White powder, mp 167e169 ꢂC; 1H NMR
mental analysis calcd (%) for C13H14Cl2N2O: C 54.75, H 4.95, N 9.82;
found: C 54.77, H 4.95, N 9.79.
(300 MHz, CDCl3):
d
¼1.49 (3H, t, J¼7.0), 2.17 (6H, s), 2.53 (3H, s),
4.57 ppm (2H, q, J¼7.0); 13C NMR (75 MHz, CDCl3):
¼18.5 (q), 19.0
d
(q), 19.8 (q), 44.0 (t), 126.1 (s), 127.2 (s), 133.6 (s), 156.6 (s), 168.2 (s),
176.9 (s) ppm (s); IR (Nujol):
elemental analysis calcd (%) for C14H14Cl2N2O3: C 51.08, H 4.29, N
8.51; found: C 51.11, H 4.29, N 8.57.
4.5. Reaction between nitrile oxide 1 and di- or trisubstituted
ethylenes dipolarophiles in boiling water: general procedure
n
¼1740 cmꢀ1; MS: m/z: 328 [Mþ];
A mixture of 1 (0.12 g, 0.52 mmol), the appropriate di- or tri-
substituted dipolarophile (0.78 mmol) in water (3.5 mL) was
refluxed for the time indicated in Table 3 under vigorous me-
chanical shaking. The resulting mixture was cooled at room tem-
perature and filtered. The solid material was washed with water
(2ꢃ5 mL) and dried in vacuo. Further crystallisation with diiso-
propyl ether gave pure 7e13, respectively.
4.3. Reaction between nitrile oxide 1 and monosubstituted
dipolarophiles in water and in the presence of SDS: general
procedure
A mixture of 1 (0.12 g, 0.52 mmol), the appropriate mono-
substituted dipolarophile (0.78 mmol) and sodium dode-
cylsulfate (SDS) (15.1 mg, 52.4
mechanically shaken at room temperature for the time indicated
m
mol) in water (3.5 mL) was
4.5.1. 3-(2,4,6-Trimethyl-3,5-dichloro)phenyl-4(R*),5(S*)-diphenyl-
4,5-dihydroisoxazole 7. White powder, mp 89e90 ꢂC; 1H NMR

G. Molteni, P. Del Buttero / Tetrahedron 67 (2011) 7343e7347
7347
(300 MHz, CDCl3):
d
¼2.28 (6H, s), 2.48 (3H, s), 4.74 (1H, d, J¼9.6),
CDCl3/D2O):
d
¼18.5 (q), 19.0 (q), 19.5 (q), 25.0 (q), 25.3 (t), 27.0
6.15 (1H, d, J¼9.6), 6.88e7.26 ppm (10H, m); 13C NMR (75 MHz,
(q), 37.8 (s), 46.9 (d), 50.0 (d), 61.7 (d), 73.0 (d), 89.8 (s), 128.6 (s),
133.5 (s), 134.2 (s), 135.6 (s), 157.2 ppm (s); IR (Nujol):
CDCl3):
d
¼18.3 (q),18.9 (q), 66.2 (d), 88.0 (d),123e129 (m),133.1 (s),
134.3 (s), 135.8 (s), 136.5 (s), 138.9 (s), 141.0 (s), 158.0 ppm (s); IR
n
¼3420 cmꢀ1; MS: m/z: 381 [Mþ]; elemental analysis calcd (%)
(Nujol):
n
¼1970, 1840 cmꢀ1; MS: m/z: 409 [Mþ]; elemental analysis
for C20H25Cl2NO2: C 62.83, H 6.59, N 3.66; found: C 62.86, H 6.61,
N 3.70.
calcd (%) for C24H21Cl2NO: C 70.25, H 5.16, N 3.41; found: C 70.26, H
5.19, N 3.48.
4.5.7. 1-(2,4,6-Trimethyl-3,5-dichloro)phenyl-3a(R)-methyl-5,5-
4.5.2. 3-(2,4,6-Trimethyl-3,5-dichloro)phenyl-4(R*),5(R*)-diphenyl-
dimethyl-7-oxo-7a(S)-bicyclo[3.1.1] heptano[4,5-c]isoxazole 13. Clear
4,5-dihydroisoxazole 8. White powder, mp 114e116 ꢂC; 1H NMR
prisms, mp 131e134 ꢂC; ½a D25
ꢄ
ꢀ63.3 (c 0.13, CH2Cl2); 1H NMR
(300 MHz, CDCl3):
d
¼1.97 (6H, s), 2.47 (3H, s), 4.43 (1H, d, J¼5.6),
(300 MHz, CDCl3):
d
¼0.96 (3H, s), 1.48 (3H, s), 1.64 (3H, s), 2.12 (3H,
6.06 (1H, d, J¼5.6), 7.19e7.54 ppm (10H, m); 13C NMR (75 MHz,
s), 2.25 (3H, s), 2.33 (3H, s), 2.42e2.69 (4H, m, overlapping),
CDCl3):
d
¼18.2 (q), 19.0 (q), 66.9 (d), 88.5 (d), 124e129 (m), 133.5
3.67 ppm (1H, s); 13C NMR (75 MHz, CDCl3):
d¼18.4 (q), 18.8 (q),19.5
(s), 133.9 (s), 135.4 (s), 136.3 (s), 137.4 (s), 140.7 (s), 158.3 ppm (s); IR
(q), 24.9 (q), 25.4 (t), 27.6 (q), 37.7 (s), 46.6 (d), 49.5 (d), 67.1 (d), 92.4
(s), 127.7 (s), 133.4 (s), 134.6 (s), 135.1 (s), 156.0 (s), 163.1 ppm (s); IR
(Nujol):
n
¼1990, 1820 cmꢀ1; MS: m/z: 409 [Mþ]; elemental analysis
calcd (%) for C24H21Cl2NO: C 70.25, H 5.16, N 3.41; found: C 70.28, H
5.16, N 3.45.
(Nujol):
n
¼1690 cmꢀ1; MS: m/z: 379 [Mþ]; elemental analysis calcd
(%) for C20H23Cl2NO2: C 63.16, H 6.10, N 3.68; found: C 63.19, H 6.12,
N 3.72.
4.5.3. 3-(2,4,6-Trimethyl-3,5-dichloro)phenyl-4(R*),5(R*)-bis-me-
thoxycarbonyl-4,5-dihydroisoxazole 9. Pale yellow powder, mp
124e127 ꢂC; 1H NMR (300 MHz, CDCl3):
d
¼2.24 (6H, s), 2.54 (3H, s),
3.63 (3H, s), 3.88 (3H, s), 4.63 (1H, d, J¼6.4), 5.62 ppm (1H, d, J¼6.4);
13C NMR (75 MHz, CDCl3):
¼18.3 (q), 19.0 (q), 53.2 (q), 60.1 (t), 81.0
Acknowledgements
Thanks are due to MURST (FIRST) for financial support. We are
grateful to Dr. Lara de Benassuti, University of Milan, for NOESY
experiments.
d
(d), 126.5 (s), 133.5 (s), 133.7 (s), 136.2 (s), 153.0 (s), 166.7 (s),
169.2 ppm (s); IR (Nujol):
mental analysis calcd (%) for C16H17Cl2NO5: C 51.35, H 4.58, N 3.74;
found: C 51.35, H 4.61, N 3.79.
n
¼1735 cmꢀ1; MS: m/z: 373 [Mþ]; ele-
References and notes
4.5.4. 1-(2,4,6-Trimethyl-3,5-dichloro)phenyl-3a(R*),4,5,6,7,7a(R*)-
hexahydro-pyrano[4,5-b]isoxazole 10. Pale yellow powder, mp
1. (a) Molteni, G. Heterocycles 2006, 68, 2177; (b) Butler, R. N.; Coyne, A. G. Chem.
Rev. 2010, 110, 6302; (c) Moulay, C.; Touati, A. C. R. Chim. 2010, 13, 1474.
2. Grundmann, C.; Richter, R. J. Org. Chem. 1967, 32, 2308.
79e81 ꢂC; 1H NMR (300 MHz, CDCl3):
d
¼1.50e2.60 (4H, m,
3. (a) Bala, K.; Hailes, H. C. Synthesis 2005, 3423; (b) Lubineau, A.; Bouchain, G.;
Queneau, Y. J. Chem. Soc., Perkin Trans. 1 1995, 2433; (c) Wijnen, J. W.; Steiner, R.
A.; Engberts, J. B. F. N. Tetrahedron Lett. 1995, 36, 5389.
overlapping), 2.25 (6H, s), 2.54 (3H, s), 3.45e3.60 (2H, m), 3.93
(1H, d, J¼5.7), 5.74 ppm (1H, d, J¼5.7); 13C NMR (75 MHz, CDCl3):
ꢁ
ꢁ
ꢁ
4. (a) Gil, M. V.; Arevalo, M. J.; Lopez, O Synthesis 2007, 1589; (b) Moses, J. E.;
Moorhouse, A. D. Chem. Soc. Rev. 2007, 36, 1249; (c) Meldal, M.; Tornøe, C. W.
Chem. Rev. 2008, 108, 2952.
d
¼18.5 (q), 19.0 (q), 21.8 (t), 25.3 (t), 48.7 (t), 62.8 (d), 100.0 (d),
127.7 (s), 133.1 (s), 134.0 (s), 135.8 (s), 161.4 ppm (s); IR (Nujol):
¼1030 cmꢀ1; MS: m/z: 313 [Mþ]; elemental analysis calcd (%) for
5. Belen’kii, L. I. In Nitrile Oxides, Nitrones and Nitronates in Organic Synthesis: Novel
Strategies in Synthesis; Feuer, H., Ed.; John: Hoboken, New Jersey, 2008; pp 1e129.
6. Inoue, Y.; Araki, K.; Shiraishi, S. Bull. Chem. Soc. Jpn. 1991, 64, 3079.
7. (a) Rolhoff, J. C.; Robinson, J., III; Gardner, J. O. Tetrahedron Lett. 1992, 33, 3113; (b)
Scobie, M.; Threadgill, M. D. J. Org. Chem.1994, 59, 7008; (c) Mineno, T.; Miller, M. J. J.
n
C15H17Cl2NO2: C 57.34, H 5.45, N 4.46; found: C 57.35, H 5.48, N
4.50.
€
Org. Chem. 2003, 68, 6591; (d) Zerresen, A.; Jaschke, A. J. Mol. Evol. 2005, 61, 236.
4.5.5. 1-(2,4,6-Trimethyl-3,5-dichloro)phenyl-3a(R*),7a(R*)-bicyclo
8. Adembri, G.; Poli, M. L.; Sega, A. J. Chem. Res., Synop. 2003, 126.
9. Lee, G. A. Synthesis 1982, 508.
10. Beltrame, P.; Veglio, C.; Simonetta, M. J. Chem. Soc. B 1967, 867.
11. (a) Lazaridis, T. Acc. Chem. Res. 2001, 34, 931; (b) Breslow, R. Acc. Chem. Res. 1991,
24, 159.
[2.2.1]heptano[4,5-c]isoxazole 11. White powder, mp 88e89 ꢂC; 1H
NMR (300 MHz, CDCl3):
s), 2.55 (3H, s), 3.44 (1H, dd, J¼6.1, 4.4), 5.27 ppm (1H, d, J¼6.1, 4.8);
13C NMR (75 MHz, CDCl3):
¼18.1 (q),18.8 (q), 22.8 (t), 42.4 (d), 49.2
d¼0.80e1.58 (6H, m), 2.23 (6H, s), 2.81 (2H,
d
12. (a) Houk, K. N.; Sims, J.; Duke, R. E.; Strozier, R. W.; George, J. K. J. Am. Chem. Soc.
1973, 95, 7287; (b) Houk, K. N.; Sims, J.; Watts, C. R.; Luskus, L. J. J. Am. Chem.
Soc. 1973, 95, 7301; (c) Houk, K. N.; Caramella, P. J. Am. Chem. Soc. 1976, 98, 6397.
13. Curran, D. P.; Kim, B. H.; Piyasena, H. P.; Loncharic, R. J.; Houk, K. N. J. Org. Chem.
1987, 52, 2137.
14. A solution of 1 (0.20 g, 0.86 mmol) and ethyl acrylate (90 mg, 0.90 mmol) or eth-
ylvinyl ether (64 mg, 0.90 mmol) in carbon tetrachloride (3.5 mL) was refluxed for
7 h. Evaporation of the solvent gave a residue, which was chromatographed on
a silica gel column with ethyl acetate/hexane 1:1. Further crystallisation with dii-
sopropyl ether gave pure 2a (0.21 g, 72%) or 2d (0.18 g, 68%), respectively.
15. van Mersbergen, D.; Wijnen, J. W.; Engberts, J. B. F. N. J. Org. Chem. 1998, 63, 8801.
16. (a) Molteni, G.; Ponti, A.; Orlandi, M. New J. Chem. 2002, 26,1340; (b) Molteni, G.;
Orlandi, M.; Broggini, G. J. Chem. Soc., PerkinTrans.12000, 3742; (c) Chatterjee, A.;
Hota, S. K.; Banerjee, M.; Bhattacharya, P. K. Tetrahedron Lett. 2010, 51, 6700.
17. De Benassuti, L.; Garanti, L.; Molteni, G. Tetrahedron 2004, 60, 4627.
(t), 55.1 (d), 80.8 (d), 126.6 (s), 128.7 (s), 133.1 (s), 135.5 (s),
156.2 ppm (s); IR (Nujol):
elemental analysis calcd (%) for C17H19Cl2NO: C 62.97, H 5.91, N
4.32; found: C 63.01, H 5.95, N 4.28.
n
¼850, 730 cmꢀ1; MS: m/z: 323 [Mþ];
4.5.6. 1-(2,4,6-Trimethyl-3,5-dichloro)phenyl-3a(R)-methyl-5,5-
dimethyl-7(S)-hydroxy-7a(S)-bicyclo [3.1.1]heptano[4,5-c]isoxazole
12. Clear prisms, mp 147e148 ꢂC; ½a D25
ꢄ
ꢀ31.0 (c 0.10, CH2Cl2); 1H
NMR (300 MHz, CDCl3/D2O):
d
¼1.11 (3H, s), 1.35 (3H, s), 1.56 (3H,
s), 2.0e2.6 (4H, m, overlapping), 2.32 (6H, s), 2.54 (3H, s), 3.29
(1H, d, J¼3.3), 3.90 ppm (1H, dd, J¼3.3, 2.0); 13C NMR (75 MHz,