Nitrile oxide 1,3-dipolar cycloadditions in water: Novel isoxazoline and cyclophane synthesis

Article abstract of DOI:10.1055/s-2005-918471

Facile examples of one-pot 1,3-dipolar cycloadditions in water are described to generate novel benzopyran, quinoline and cyclophane isoxazolines. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2005-918471

PAPER
3423
Nitrile Oxide 1,3-Dipolar Cycloadditions in Water: Novel Isoxazoline and
Cyclophane Synthesis
N
itrile-Oxide 1,3-
a
ipolar Cyc
s
loadditio
o
ns in
W
ater n Bala, Helen C. Hailes*
Department of Chemistry, University College London, 20 Gordon Street, London WC1H 0AJ, UK
Fax +44(20)76797463; E-mail: h.c.hailes@ucl.ac.uk
Received 14 September 2005
only as a medium is less common. Examples include work
by Rohloff et al. who used dibromoformaldoxime in a
one-pot reaction which decomposed to a nitrile oxide in
alkaline water and was then coupled to water-soluble ole-
fins and acetylenes.8 Also the reaction of a benzonitrile N-
oxide with a cyclodextrin-supported alkene terminated
acylamide, however, as is often the case the nitrile oxide
was preformed.9 Nevertheless, there are significant ad-
vantages to using water alone as a solvent including facile
product isolation if it has a low solubility in water. Herein
we describe studies to investigate the feasibility of using
water as a reaction solvent in a one-pot reaction for the in-
tramolecular 1,3-dipolar cycloaddition of 1 to generate
benzopyran and quinoline-based isoxazolines 2, useful
synthetic intermediates for the synthesis of bifunctional
compounds. The effect of substrate hydrophobicity
through incorporation of a hydrophilic spacer has also
been explored.
Abstract: Facile examples of one-pot 1,3-dipolar cycloadditions in
water are described to generate novel benzopyran, quinoline and cy-
clophane isoxazolines.
Key words: pericyclic reaction, 1,3-dipolar cycloaddition, cyclo-
phane, nitrile oxide, reactions in water
The use of water as a solvent for organic reactions offers
many potential advantages over organic solvents includ-
ing safety and cost. In the early 1980s Breslow and Ride-
out highlighted other benefits of using water for Diels–
Alder reactions where rate enhancements and different
stereoselectivities were observed.1 These were attributed
to the hydrophobic effect,1,2 and since then the use of
aqueous media has been exploited in a wide range of or-
ganic transformations: the importance of hydrogen bond
interactions has also been recognised.3 Another pericyclic
reaction, the 1,3-dipolar cycloaddition has by comparison
not been extensively investigated in aqueous media. The
formation and reactivity of substituted benzonitrile oxides
in aqueous solution was first reported by Hegarty et al.,
who highlighted that benzohydroxamoyl chloride could
be converted to the corresponding 1,3-dipole in water
which was then used as a medium for the cycloaddition.4
Lee subsequently reported the cyclization of nitrile oxides
with dipolarophiles in aqueous–organic biphasic systems
through generation of the nitrile oxide from the corre-
sponding oxime in situ: several of the cycloadditions also
required the addition of a catalytic amount of organic
base, typically triethylamine.5 The reaction of preformed
2,6-dichlorobenzonitrile N-oxide with 2,6-diisopropyl-p-
benzoquinone has been described in aqueous ethanol mix-
tures where enhanced rates were observed compared to
that in chloroform.6 However, a more recent kinetic study
explored the pericyclic reaction between preformed ben-
zonitrile N-oxide and a range of dipolarophiles in aqueous
and organic media.7 It was concluded that with electron-
rich dipolarophiles the cycloaddition was accelerated in
water and protic solvents, but no special effects were ob-
served with electron-poor dipolarophiles.7
In
initial
experiments
2-{[(E)-3-phenylprop-2-
enyl]oxy}benzaldehyde, selected as a substrate to give an
aromatic group on the isoxazoline cycloadduct, was pre-
pared as previously reported.10 The benzaldoxime 1a was
readily formed using hydroxylamine in 97% yield and
found to be relatively insoluble in a number of organic
solvents, however was sparingly soluble in THF. The ad-
dition of sodium hypochlorite in water to 1a in THF re-
sulted in the formation of 2a in 90% yield (Scheme 1,
Table 1, entry 1). When the reaction was performed in wa-
ter only under the same conditions 2a was formed in 24%
yield, but extension of the reaction time increased the
yield to 90% (Table 1, entries 2,3). No nitrile oxide inter-
mediates or side-products were isolated. Notably, one key
advantage of using water was that the product 2a could be
isolated directly by filtration, rather than phase separation
and removal of the organic solvent, and no undissolved
starting material remained. Also in these cycloadditions,
the addition of a base was not required as had been report-
ed by Lee who converted o-allyloxybenzaldoxime to the
corresponding benzopyran in a biphasic reaction system.5
H
O
N
Biphasic or homogeneous mixed solvent systems have
been used when carrying out 1,3-dipolar cycloaddition re-
actions in aqueous media and the application of water
OH
Ph
a
N
H
X
Ph
X
1a X = O
1b X = NH
2a X = O
2b X = NH
SYNTHESIS 2005, No. 19, pp 3423–3427
x
x.
x
x
.
2
0
0
5
Advanced online publication: 14.11.2005
DOI: 10.1055/s-2005-918471; Art ID: C07105SS
© Georg Thieme Verlag Stuttgart · New York
Scheme 1 Reagents and conditions: a) solvent and time (see Table
1), r.t., NaOCl

3424
K. Bala, H. C. Hailes
PAPER
Table 1 Reaction Conditions and Results for 1,3-Dipolar Cycload-
OH
NH2
ditions in Scheme 1a
d,e
OH
a–c
1b
N
Ph
Entry Conditions
Time (h) Product Yield (%)
H
3
1
2
H2O–THF (3:7)
18
18
72
18
18
18
72
72
18
18
48
18
2a
2a
2a
2a
2a
2a
2a
–
90
25
90
33
60
91
24
0
Scheme 2 Reagents and conditions: a) CH2Cl2, TBDMSCl, Et3N,
r.t., 18 h (90%); b) (E)-cinnamaldehyde, toluene, Dean–Stark
apparatus, 18 h (97%); c) NaBH3CN, HCl to pH 2, r.t., 10 h (96%);
d) Fetizon’s reagent, toluene, Dean–Stark apparatus, 18 h (95%);
e) NH2OH·HCl, NaOH, EtOH–H2O (4:1) (97%)
H2O
3
H2O
4
H2O–THF (9:1)
H2O–THF (1:1)
H2O–THF (1:9)
90 mM SDS in H2O
CH2Cl2/H2O (95:5)
CH2Cl2/H2O (9:1)
H2O
isoxazoline 2b from benzaldoxime 1b was explored.
Compound 1b was prepared as shown in Scheme 2.
5
6
2-Aminobenzyl alcohol was protected using tert-butyl-
dimethylsilyl chloride, then reacted with (E)-cinnamalde-
hyde to give the imine as previously described.13
Reduction of the imine was carried out using sodium cy-
anoborohydride under acidic conditions14 which also led
to removal of the silyl protecting group in 96% yield to
give 3. Finally, oxidation to the aldehyde using Fetizon’s
reagent15 and reaction with hydroxylamine gave the benz-
aldoxime 1b in high yield.
7
8
9
2b
2b
2b
2b
90
40
92
40
10
11
12
H2O
90 mM SDS in H2O
In situ formation of the nitrile oxide precursor and 1,3-di-
polar cycloaddition were then explored. Compound 1b
was soluble in dichloromethane which was used in initial
studies. Accordingly, dichloromethane/water (95:5) as
solvent and sodium hypochlorite as the oxidant readily led
to formation of the isoxazoline in 90% yield (Scheme 1,
Table 1, entry 9). Using water alone as a solvent led to the
formation of 2b under the same conditions in 40% yield,
however, on extending the reaction time 2b was isolated
in 92% yield (Table 1, entries 10 and 11). Both the benzal-
doxime and product had low solubilities in water and no
intermediates such as the nitrile oxide were isolated.
Again this suggested that the solubility of 1b in water may
reduce the rate of chlorination and subsequent nitrile ox-
ide formation, however, the ease of product isolation at
the end of the reaction by filtration made the reaction ex-
tremely facile. Use of the surfactant SDS had no effect on
solubilising the oxime and the product 2b was isolated in
the same yield as when water was alone used (Table 1, en-
try 12).
a NaOCl (2.5 equiv as 11% aqueous solution) was used.
Further investigations into the effect of water on the reac-
tion were carried out using different ratios of water–THF
as the solvent. An increased proportion of water led to a
suppression of the cycloaddition reaction and formation
of the adduct 2a in a lower yield (Table 1, entries 4–6).
The use of aqueous surfactant media was explored to en-
hance solubilisation of the benzaldoxime 1a with sodium
dodecyl sulfate (SDS) solution.11 No effect was observed,
1a still had low solubility in the aqueous media and 2a
was isolated in 24% yield (Table 1, entry 7). When dichlo-
romethane–water was used as a solvent no reaction was
observed perhaps reflecting the poor solubility of 1a in
dichloromethane (Table 1; entry 8).
For comparison purposes, the formation of the nitrile ox-
ide was investigated using Grundmann’s methodology12
with subsequent cyclisation. Initially 1a was treated with
N-bromosuccinimide and triethylamine in anhydrous
DMF but no cyclised product was generated. Modifica-
tion of the reaction conditions, using aqueous ethanol
rather than DMF and sodium hydroxide as base generated
the cyclised product 2a after 18 hours in 24% yield. Over-
all, the outcome of these reactions is likely to be a balance
between the enforced aggregation of reacting functional-
ities as a consequence of the hydrophobic effect, since the
reaction proceeds more readily in aqueous-based media,
and hydrogen-bond interactions and the solubilities of
starting material and product. The one-pot reaction could
readily be performed in water alone, ensuring the facile
isolation of product, however the reactions proceeded
more slowly in water than in a biphasic THF–water mix-
ture.
Having established a straightforward protocol for synthe-
sis of the isoxazolines in water, the methodology was ex-
tended to the synthesis of a novel cyclophane where it was
envisaged that performing the cycloaddition reaction in
water and exploiting any templating effects may be of
benefit. Accordingly the benzaldoxime precursor 4 was
prepared (Scheme 3): 2-allyloxyethanol was activated
with methanesulfonyl chloride which was coupled to sal-
icylaldehyde in 75% yield. Reaction with hydroxylamine
hydrochloride generated the benzaldoxime 4 in high yield
as before which appeared to have limited solubility in wa-
ter, although on mixing with sodium hypochlorite resulted
in formation of a homogeneous solution from which a pre-
cipitate was generated. After 18 hours, a product was iso-
lated and determined to be the dimeric species 5, formed
in 97% yield. Compound 5 existed as a mixture of two
diastereoisomers (ratio 4:1 by analytical HPLC). A com-
Having established the feasibility of using water alone as
a solvent, formation of the corresponding quinoline-based
Synthesis 2005, No. 19, 3423–3427 © Thieme Stuttgart · New York

PAPER
Nitrile Oxide 1,3-Dipolar Cycloadditions in Water
3425
dium (THF). Anhyd DMF (Aldrich) was used as received. 1H NMR
spectra were recorded on a Bruker instrument at 300 MHz, 400
MHz or 500 MHz as indicated, and 13C NMR spectra at 75 MHz or
125 MHz. Residual protic solvent was taken as internal standard
with CDCl3. Mass spectrometry was performed at UCL (EI, FAB)
or London School of Pharmacy using an Autospec Q, VG 7070, VG
7070B or a ZAB-SE instrument. High resolution accurate mass
spectra were performed at the London School of Pharmacy (FAB).
Elemental analyses were carried out at the UCL microanalytical ser-
vice. IR were recorded on a Perkin-Elmer 983G or FT-IR 1605 in-
strument. Melting points were determined using a Gallenkamp
melting point apparatus and are uncorrected. HPLC analyses were
performed using a Gilson M303 instrument and a HiChrom normal
phase column and UV-visible detector.
parable yield and isomer ratio were observed when using
a mixed dichloromethane/water (95:5) solution contain-
ing sodium hypochlorite for the reaction, and in both cases
no monomeric cycloadducts were isolated. This was most
likely due to complexation of the ethylene glycol units
from each unit around sodium during the cyclisation. To
confirm the effect of sodium cations, treatment of 4 with
N-bromosuccinimide and triethylamine in DMF to gener-
ate the nitrile oxide then afforded 5 in only 10% yield, to-
gether with a resinous material, most likely a polymer.
This confirmed that the chelation effect by sodium en-
hances formation of the dimeric species rather than poly-
merization. Notably, related benzaldoximes comprised of
aliphatic spacers have undergone 1,3-dipolar cycloaddi-
tion in organic media: monomeric isoxazoles were formed
in low yield together with traces of a dimer (depending on
the spacer used) and large quantities of a polymer.16 Our
approach highlights the highly selective nature of the re-
action through the incorporation of ethylene glycol units
and use of aqueous media for a one-pot reaction.
2-{[(E)-3-Phenylprop-2-enyl]oxy}benzaldehyde was prepared as
previously described.10 2-(tert-Butyldimethylsilyloxymethyl)phe-
nyl-1-amine and 2-(tert-butyldimethylsilyloxymethyl)phenyl-1-
[(E)-3-phenylprop-2-enylidene]imine were prepared as previously
reported.13
2-{[(E)-3-Phenylprop-2-enyl]oxy}benzaldehyde Oxime (1a)
2-{[(E)-3-Phenylprop-2-enyl]oxy}benzaldehyde (6.00 g, 25.2
mmol), NaOH (5.00 g, 125 mmol) and NH2OH·HCl (2.74 g, 39.4
mmol) were added to a solution of 80% aq EtOH (50 mL) and the
mixture stirred at r.t. for 8 h. The crude product was extracted into
EtOAc (3 × 25 mL) and the combined organic extracts dried
(MgSO4). The solvent was removed in vacuo and the crude product
recrystallised from EtOH to afford 1a as yellow crystals (6.18 g,
97%); mp 104–106 °C (EtOH).
H
OH
N
O
a–c
HO
O
O
O
4
IR (KBr): 3293, 2960, 1593 cm–1.
d
N
O
1H NMR (300 MHz, CDCl3): d = 4.67 (2 H, dd, J = 5.7, 1.2 Hz,
CH2O), 6.32 (1 H, td, J = 16.0, 5.7 Hz, =CHCH2O), 6.66 (1 H, d,
J = 16.0 Hz, C=CHPh), 6.91 (2 H, m, ArH), 7.20–7.36 (6 H, m,
ArH), 7.77 (1 H, dd, J = 8.0, 1.6 Hz, ArH), 8.52 (1 H, s, HC=N).
13C NMR (75 MHz, CDCl3): d = 69.2 (CH2O), 112.6 (C-3), 121.1,
124.1, 126.6, 126.8, 128.0, 128.3, 128.6, 131.1, 133.2, 136.3, 146.6,
156.8.
O
O
O
5
O
N
MS (EI): m/z (%) = 253 (M+, 3), 236 (10), 117 (100).
HRMS: m/z calcd for C16H16NO2 [MH+]: 254.1181; found:
Scheme 3 Reagents and conditions: a) MeSO2Cl (95%); b) salicyl-
aldehyde (75%), NaH, DMF; c) NH2OH·HCl, NaOH, EtOH–H2O
(4:1) (97%); d) NaOCl (2.5 equiv as 11% aqueous solution) (97%)
254.1170.
Anal. Calcd for C16H15NO2: C, 75.87; H, 5.97; N, 5.53. Found: C,
75.49; H, 5.90; N, 5.42.
In summary, facile examples of one-pot 1,3-dipolar cy-
cloadditions have been described in water to generate a
novel benzopyran, quinoline and cyclophane isoxazoline.
The reaction times to form 2a and 2b were longer using
water alone as a solvent rather than a mixed solvent sys-
tem, perhaps reflecting the low solubilities of the benzal-
doximes in water. One major advantage of using water
was the ease of isolation because the products precipitated
out of solution and no starting material remained. Also
when using aqueous media, the novel cyclophane was
formed without formation of polymeric side-products.
This approach can now be applied to the formation of re-
lated materials including cyclophanes comprised of alter-
native ring sizes.
3-Phenyl-3a,4-dihydro-3H-chromeno[4,3-c]isoxazole (2a)
To 1a (0.253 g, 1.00 mmol) in the solvent indicated (Table 1, 15
mL) was added aq NaOCl (11% Cl2 content, 1.62 mL, 2.50 mmol)
at 5 °C. The reaction was stirred for 10 min, then at r.t. for 18 h.
When an organic solvent was used, H2O (30 mL) was added, the or-
ganic layer separated and remaining product extracted from the
aqueous layer using CH2Cl2 (15 mL). The combined organic ex-
tracts were washed with H2O (15 mL), dried (MgSO4) and the sol-
vent was removed in vacuo. The crude product was purified by
precipitation with cold Et2O to afford 2a as colourless crystals.
When H2O was used as a reaction solvent, the precipitate formed
was isolated by filtration under reduced pressure and washed with
cold Et2O (2 × 5 mL) to give 2a; mp 80–82 °C (Et2O).
IR (KBr): 2954, 1649, 1607, 1500 cm–1.
1H NMR (300 MHz, CDCl3): d = 3.82 (1 H, ddd, J = 12.6, 12.3, 5.8
Hz, 3a-H), 4.15 (1 H, dd, J = 12.3, 10.4 Hz, CHHO), 4.50 (1 H, dd,
J = 10.4, 5.8 Hz, CHHO), 5.15 (1 H, d, J = 12.6 Hz, 3-H), 6.85 (1
H, d, J = 8.4 Hz, 6-H), 6.91 (1 H, dd, J = 7.7, 7.3 Hz, 8-H), 7.24 (1
H, ddd, J = 8.4, 7.3, 1.6 Hz, 7-H), 7.34 (5 H, m, C6H5), 7.76 (1 H,
dd, J = 7.7, 1.6 Hz, 9-H).
Chemicals were purchased from Aldrich or Lancaster and used as
received. Unless otherwise stated, H2O refers to the use of deionised
H2O. Solvents were purchased from BDH Ltd unless indicated oth-
erwise and used as received. Anhyd reaction solvents were HPLC
grade and freshly distilled over CaH2 (CH2Cl2, toluene, Et3N) or so-
Synthesis 2005, No. 19, 3423–3427 © Thieme Stuttgart · New York

3426
K. Bala, H. C. Hailes
PAPER
13C NMR (75 MHz, CDCl3): d = 53.0 (C-3a), 69.2, 85.9, 113.3,
117.6, 122.0, 125.7, 126.7, 129.01, 129.04, 132.6, 137.4, 153.4,
156.7.
FAB-MS: m/z (%) = 252 (MH+, 100), 236 (10), 117 (100).
HRMS: m/z calcd for C16H14NO2 [MH+]: 252.1025; found:
and dried (MgSO4). The solvent was removed in vacuo to yield 1b
as a yellow oil (0.42 g, 97%).
IR (film): 3332, 2950, 1616, 1575, 1520 cm–1.
1H NMR (300 MHz, CDCl3): d = 4.02 (2 H, dd, J = 5.3, 4.3 Hz,
CH2N), 6.26 (1 H, td, J = 16.0, 5.3 Hz, NCH2CH), 6.65 (1 H, d,
J = 16.0 Hz, CHPh), 6.68 (2 H, m, Ar 3-H, 5-H), 7.01 (1 H, br s),
7.11 (1 H, m, Ar 4-H), 7.20–7.40 (6 H, m, ArH), 8.23 (1 H, CH=N).
252.1015.
2-[(E)-3-Phenylprop-2-enylamino)]phenylmethanol (3)
13C NMR (75 MHz, CDCl3): d = 45.6 (CH2N), 111.0, 114.6, 115.9,
126.7, 127.0, 127.9, 128.9, 131.3, 131.8, 133.2, 137.3, 147.6 (C=N),
154.7.
MS (EI): m/z (%) = 252 (M+, 25), 235 (90), 117 (100).
HRMS: m/z calcd for C16H17N2O [MH+]: 253.1341; found:
To a solution of NaBH3CN (0.28 g, 4.44 mmol) in aq acidic MeOH
(pH 2, 10 mL) was added 2-(tert-butyldimethylsilyloxymethyl)phe-
nyl-1-[(E)-3-phenylprop-2-enylidene]imine13 (1.00 g, 2.96 mmol).
The mixture was stirred at r.t. for 10 h and the solvent removed in
vacuo. On addition of H2O (10 mL), the crude product was extract-
ed into EtOAc (3 × 20 mL), washed with brine (2 × 20 mL), H2O
(20 mL) and the combined organic extracts were dried (MgSO4).
The solvent was removed in vacuo and the product was purified us-
ing flash silica chromatography (EtOAc–hexane, 2:1) to give 3 as
yellow crystals (0.68 g, 96%); mp 124–126 °C (EtOAc–hexane).
253.1350.
3-Phenyl-3,3a,4,5-tetrahydroisoxazolo[4,3-c]quinoline (2b)
To a solution of 1b (60 mg, 0.24 mmol) in solvent (5.85 mL) was
added aq NaOCl (11% Cl2 content, 0.65 mL, 1.00 mmol) at 5 °C.
The mixture was stirred at r.t. for 18 h. When an organic solvent was
used, H2O (10 mL) was added, the organic layer was separated and
remaining product was extracted from the aqueous layer using
CH2Cl2 (10 mL). The combined organic extracts were washed with
H2O (10 mL), dried (MgSO4) and the solvent was removed in vac-
uo. The crude product was purified by precipitation with cold Et2O
to afford 2b as yellow crystals. When H2O was used as a reaction
solvent, the precipitate formed was isolated by filtration under re-
duced pressure and washed with cold Et2O (2 × 5 mL) to give 2b;
mp 110–112 °C (Et2O).
IR (KBr): 3490, 2840, 1651, 1574, 1512 cm–1.
1H NMR (500 MHz, CDCl3): d = 3.90 (2 H, dd, J = 5.8, 1.6 Hz,
CH2N), 4.60 (2 H, s, CH2OH), 6.28 (1 H, dt, J = 15.9, 5.8 Hz,
NCH2CH), 6.55 (1 H, d, J = 15.9 Hz, CHPh), 6.60 (1 H, ddd,
J = 8.1, 7.4, 1.3 Hz, Ar 5-H), 6.65 (1 H, d, J = 8.1 Hz, Ar 3-H), 6.99
(1 H, dd, J = 7.4, 1.3 Hz, Ar 6-H), 7.15–7.29 (6 H, m, ArH).
13C NMR (125 MHz, CDCl3): d = 45.7 (CH2N), 64.8 (CH2OH),
111.1, 116.7, 124.5, 126.3, 127.0, 127.5, 128.5, 129.1, 129.7, 131.4,
136.9, 147.3.
MS (EI): m/z (%) = 239 (M+, 15), 220 (16), 117 (100).
IR (KBr): 3387, 2885, 1612, 1497 cm–1.
HRMS: m/z calcd for C16H17NO [M+]: 239.1310; found: 239.1300.
1H NMR (300 MHz, CDCl3): d = 3.31 (1 H, dd, J = 12.5, 10.8 Hz,
CHHN), 3.48 (1 H, dd, J = 10.8, 5.8 Hz, CHHN), 3.62 (1 H, ddd,
J = 12.5, 12.2, 5.8 Hz, 3a-H), 4.06 (1 H, br s, NH), 5.22 (1 H, d,
J = 12.2 Hz, 3-H), 6.48 (1 H, d, J = 8.4 Hz, 6-H), 6.60 (1 H, dd,
J = 7.8, 7.3 Hz, 8-H), 7.05 (1 H, ddd, J = 8.4, 7.3, 1.2 Hz, 7-H), 7.29
(5 H, m, C6H5), 7.54 (1 H, dd, J = 7.8, 1.2 Hz, 9-H).
13C NMR (75 MHz, CDCl3): d = 45.6 (C-3a), 54.3 (C-4), 86.8 (C-
3), 110.9, 115.1, 118.7, 126.0, 126.7, 128.7, 128.8, 131.9, 138.1,
145.9, 155.5.
Anal. Calcd for C16H17NO: C, 80.30; H, 7.16; N, 5.85. Found: C,
80.08; H, 7.09; N, 5.69.
2-[(E)-3-Phenylprop-2-enylamino)]benzaldehyde
To a solution of 3 (1.05 g, 4.40 mmol) in anhyd toluene (50 mL) was
added Fetizon’s reagent15 (Ag2CO3/Celite 1.80 mmol/g; 4.88 g,
4.40 mmol). The reaction mixture was refluxed for 18 h with the
azeotropic removal of H2O. Insoluble material was then removed by
filtration and the filtrate was evaporated in vacuo. The crude prod-
uct was purified by flash silica chromatography (EtOAc–hexane,
1:1) to afford the title compound as a yellow oil (0.99 g, 95%).
FAB-MS: m/z (%) = 251 (MH+, 100), 233 (16), 117 (20).
HRMS: m/z calcd for C16H15N2O [MH+]: 251.1184; found:
251.1175.
IR (film): 3332, 2850, 1689, 1651, 1574, 1512 cm–1.
1H NMR (300 MHz, CDCl3): d = 3.98 (2 H, ddd, J = 5.7, 5.7, 1.5
Hz, CH2N) 6.23 (1 H, td, J = 16.0, 5.7 Hz, NCH2CH), 6.50 (1 H, d,
J = 16.0 Hz, CHPh), 6.63 (2 H, m, Ar 3-H, 5-H), 7.20–7.30 (6 H, m,
ArH), 7.40 (1 H, dd, J = 7.0, 1.5 Hz, Ar 6-H), 8.64 (1 H, br s, NH),
9.80 (1 H, s, CHO).
13C NMR (75 MHz, CDCl3): d = 44.5 (CH2N), 111.2, 115.2, 118.7,
125.7, 126.4, 127.6, 128.6, 131.7, 135.7, 136.66, 136.7, 150.6,
194.0 (C=O).
Methanesulfonic Acid 2-Propenyloxyethyl Ester
The reaction was carried out under anhydrous conditions. To prope-
nyloxyethylene glycol (6.40 mL, 60 mmol) in CH2Cl2 (50 mL) was
added MeSO2Cl (4.64 mL, 60 mmol). Et3N (8.34 mL, 60 mmol)
was then added dropwise and the mixture was stirred at r.t. for 18 h.
The triethylamine hydrochloride precipitate was removed by filtra-
tion and H2O (50 mL) was added to the filtrate. The organic layer
was separated, washed with aq sat. NaHCO3 solution (3 × 100 mL)
and brine (2 × 50 mL), then dried (MgSO4). The solvent was re-
moved in vacuo to afford the title compound as a yellow oil (10.26
g, 95%) which was used immediately in the next step.
APCI + MS: m/z (%) = 237 (M+, 15), 134 (14), 117 (100).
HRMS: m/z calcd for C16H15NO [M+]: 237.1154; found: 237.1144.
IR (film): 1649, 1457, 1418 cm–1.
Anal. Calcd for C16H15NO: C, 80.78; H, 6.37; N, 5.90. Found: C,
80.78; H, 6.24; N, 5.70.
1H NMR (300 MHz, CDCl3): d = 3.03 (3 H, s, SO3CH3), 3.65 (2 H,
t, J = 4.6 Hz, CH2CH2OSO2CH3), 3.99 (2 H, dd, J = 5.6, 1.4 Hz,
CH2OCH), 4.32 (2 H, t, J = 4.6 Hz, CH2OSO2CH3), 5.22 (2 H, dd,
J = 10.4, 1.5 Hz, CHH=CH), 5.24 (1 H, dd, J = 17.1, 1.5 Hz,
CHH=CH), 5.87 (1 H, tdd, J = 17.1, 10.4, 5.6 Hz, CH=CH2).
13C NMR (75 MHz, CDCl3): d = 37.7 (SO3CH3), 67.8, 69.1, 72.4,
118.0, 134.4.
2-[(E)-3-Phenylprop-2-enylamino]benzaldehyde Oxime (1b)
To 2-[(E)-3-phenylprop-2-enylamino]benzaldehyde (0.410 g, 1.72
mmol) in 80% aq EtOH (10 mL), were added NaOH (0.10 g, 2.60
mmol) and NH2OH·HCl (0.48 g, 4.88 mmol). The mixture was
stirred at r.t. for 18 h and then diluted with H2O (10 mL). The crude
product was extracted into EtOAc (3 × 25 mL) and the combined or-
ganic extracts were washed with brine (2 × 20 mL), H2O (20 mL)
FAB-MS: m/z (%) = 181 (MH+, 100), 123 (85), 85 (50).
HRMS: m/z calcd for C6H13O4S [MH+]: 181.0535; found: 181.0544.
Synthesis 2005, No. 19, 3423–3427 © Thieme Stuttgart · New York

PAPER
Nitrile Oxide 1,3-Dipolar Cycloadditions in Water
3427
1
2-(2-Propenyloxyethoxy)benzaldehyde
Major Diastereoisomer: H NMR (500 MHz, CDCl3): d = 3.44 (2
H, dd, J = 17.6, 7.9 Hz, 2 × N=CCHH), 3.58 (2 H, dd, J = 17.6, 10.5
Hz, 2 × N=CCHH), 3.67 (2 H, m, 2 × OCHCHHO), 3.73 (2 H, m,
2 × OCHCHHO), 3.86 (2 H, m, 2 × CHHCH2OAr), 3.95 (2 H, m,
2 × CHHCH2OAr), 4.10 (2 H, m, 2 × CHHOAr), 4.20 (2 H, m, 2 ×
CHHOAr), 4.79 (2 H, m, 2 × CHON), 6.86 (2 H, d, J = 8.5 Hz,
ArH), 6.95 (2 H, dd, J = 7.7, 7.4 Hz, ArH), 7.33 (2 H, ddd, J = 8.5,
7.4, 1.5 Hz, ArH), 7.78 (2 H, dd, J = 7.7, 1.5 Hz, ArH).
The reaction was carried out under anhydrous conditions. To
salicylaldehyde (4.88 g, 40.0 mmol) in anhyd DMF (50 mL) was
added NaH (60 wt% in mineral oil, 1.60 g, 40 mmol) and the mix-
ture was stirred at r.t. for 2 h. Methanesulfonic acid 2-propenyloxy-
ethyl ester (7.24 g, 40.0 mmol) was then added the reaction heated
at 70 °C for 18 h. On cooling, H2O was added and the crude product
was extracted into EtOAc (3 × 50 mL). The combined organic ex-
tracts were washed with aq sat. NaHCO3 solution (2 × 20 mL), brine
(20 mL), and dried (MgSO4). The solvent was removed in vacuo
and the crude product was purified by flash silica chromatography
(hexane–EtOAc, 2:1) to afford the title compound as an oil (6.18 g,
75%).
13C NMR (125 MHz, CDCl3): d = 40.7 (CH2C= N), 67.7, 69.9,
72.2, 79.5 (CHON), 111.8, 118.9, 121.0, 129.4, 131.3, 156.3, 156.5.
1
Minor Diastereoisomer: H NMR (500 MHz, CDCl3): d = 3.46 (2
H, dd, J = 17.5, 7.9 Hz, 2 × N=CCHH), 3.63 (2 H, dd, J = 17.5, 10.5
Hz, 2 × N=CCHH), 3.67 (2 H, m, 2 × OCHCHHO), 3.73 (2 H, m,
2 × OCHCHHO), 3.89 (2 H, m, 2 × CHHCH2OAr), 3.91 (2 H, m,
2 × CHHCH2OAr), 4.07 (2 H, m, CHHOAr), 4.20 (2 H, m, 2 ×
CHHOAr), 4.79 (2 H, m, 2 × CHON), 6.83 (2 H, d, J = 8.5 Hz,
ArH), 6.91 (2 H, dd, J = 7.7, 7.4 Hz, ArH), 7.31 (2 H, ddd, J = 8.5,
7.4, 1.5 Hz, ArH), 7.82 (2 H, dd, J = 7.7, 1.5 Hz, ArH).
IR (film): 2952, 1683, 1599, 1485 cm–1.
1H NMR (300 MHz, CDCl3): d = 3.88 (2 H, t, J = 4.9 Hz,
CH2CH2OAr), 3.99 (2 H, dd, J = 5.3, 1.3 Hz, CH2C=), 4.32 (2 H, t,
J = 4.9 Hz, CH2OAr), 5.22 (2 H, dd, J = 10.4, 1.3 CHH=CH), 5.24
(1 H, dd, J = 17.2, 1.3 Hz, CHH=CH), 5.87 (1 H, tdd, J = 17.1, 10.4,
5.3 Hz, CH=CH2), 6.98 (2 H, m, ArH), 7.53 (1 H, m, ArH), 7.76 (1
H, dd, J = 7.7, 1.7 Hz, Ar 6-H), 10.53 (1 H, s, CHO).
13C NMR (75 MHz, CDCl3): d = 68.7 (C-2¢, CH2OCH), 72.8, 113.3,
117.8, 121.4, 125.6, 128.7, 134.8, 136.2, 161.7, 190.1 (CHO).
FAB-MS: m/z (%) = 207 (MH+, 25), 149 (20).
13C NMR (125 MHz, CDCl3): d = 40.1 (CH2C=N), 67.2, 69.8, 71.5,
79.4, 112.0, 118.8, 121.0, 129.3, 131.3, 156.2, 156.5.
Acknowledgment
We thank AWE plc for a studentship to KB.
HRMS: m/z calcd for C12H15O3 [MH+]: 207.1021; found: 207.1030.
2-(2-Propenyloxyethoxy)benzaldehyde Oxime (4)
References
To 2-(2-propenyloxyethoxy)benzaldehyde (5.15 g, 25.0 mmol) in
80% aq EtOH (100 mL) were added NaOH (3.20 g, 80.0 mmol) and
NH2OH·HCl (5.65 g, 80.0 mmol). The mixture was stirred at r.t. for
10 h and then diluted with H2O (10 mL). The crude product was ex-
tracted into EtOAc (3 × 25 mL) and the combined organic extracts
were washed with brine (2 × 30 mL) and dried (MgSO4). The sol-
vent was removed in vacuo to yield 4 as a yellow oil (6.43 g, 97%).
(1) Rideout, D. C.; Breslow, R. J. Am. Chem. Soc. 1980, 102,
7816.
(2) (a) Tanford, C. The Hydrophobic Effect, 2nd ed.; Wiley:
New York, 1980. (b) Blokzijl, W.; Engberts, J. B. F. N.
Angew. Chem., Int. Ed. Engl. 1993, 32, 1545.
(3) For example: (a) Breslow, R. Acc. Chem. Res. 1991, 24,
159. (b) Li, C. J.; Chan, T.-H. Organic Reactions in Aqueous
Media; Wiley: New York, 1997. (c) Lubineau, A.; Augé, J.;
Queneau, Y. Synthesis 1994, 741. (d) Li, C. Chem. Rev.
1993, 93, 2023. (e) Ribe, S.; Wipf, P. Chem. Commun. 2001,
299.
(4) (a) Dignam, K. J.; Hegarty, A. F.; Quain, P. L. J. Chem. Soc.,
Perkin Trans. 2 1977, 1457. (b) Dignam, K. J.; Hegarty, A.
F.; Quain, P. L. J. Org. Chem. 1978, 43, 388.
(5) Lee, G. A. Synthesis 1982, 508.
IR (film): 3351, 2953, 1670, 1594, 1490, 1453 cm–1.
1H NMR (300 MHz, CDCl3): d = 3.82 (2 H, t, J = 4.8 Hz,
CH2CH2OAr), 4.09 (2 H, dd, J = 5.3, 1.4 Hz, CH2C=), 4.32 (2 H, t,
J = 4.8 Hz, CH2OAr), 5.22 (2 H, dd, J = 10.3, 1.3 Hz, CHH=CH),
5.24 (1 H, dd, J = 17.2, 1.3 Hz, CHH=CH), 5.87 (1 H, tdd, J = 17.2,
10.3, 5.3 Hz, CH=CH2), 6.98 (2 H, m, H-3, H-5), 7.31 (1 H, m, H-
4), 7.71 (1 H, dd, J = 7.7, 1.7 Hz, Ar 6-H), 7.74 (NOH), 8.53 (1 H,
s, CH=N).
13C NMR (75 MHz, CDCl3): d = 68.2, 68.6, 72.4, 112.6, 117.4,
121.2, 126.5, 128.3, 131.1, 134.5, 146.5, 156.9.
(6) Inoue, Y.; Araki, K.; Shiraishi, S. Bull. Chem. Soc. Jpn.
1991, 64, 3079.
(7) Van Mersbergen, D.; Wijnen, J. W.; Engberts, J. B. F. N. J.
Org. Chem. 1998, 63, 8801.
(8) Rohloff, J. C.; Robinson, J. III; Gardner, J. O. Tetrahedron
FABMS: m/z (%) = 222 (MH+, 32), 206 (12).
HRMS: m/z calcd for C12H16NO3 [MH+]: 222.1130; found:
222.1140.
Lett. 1992, 33, 3113.
(9) Meyer, A. G.; Easton, C. J.; Lincoln, S. F.; Simpson, G. W.
Chem. Commun. 1997, 1517.
(10) Aurrecoechea, J. M.; López, B.; Fernández, A.; Arrieta, A.;
Cossío, F. P. J. Org. Chem. 1997, 62, 1125.
(11) Hailes, H. C.; Diego-Castro, M. J. Tetrahedron Lett. 1998,
39, 2111.
(12) Grundmann, C. Synthesis 1970, 344.
(13) Zamboni, R.; Just, G. Can. J. Chem. 1978, 56, 2720.
(14) Orlemans, E. O. M.; Schreuder, A. H.; Conti, P. G. M.;
Verboom, W.; Reinhoudt, D. N. Tetrahedron 1987, 43,
3817.
(15) (a) Fetizon, M.; Golfien, M.; Louis, J.-M. Tetrahedron 1975,
31, 171. (b) Morgans, D. J. Tetrahedron Lett. 1981, 22,
3721.
Diisoxazoline 5
To a solution of 4 (53 mg, 0.25 mmol) in H2O (5.85 mL) was added
aq NaOCl (11% Cl2 content; 0.65 mL, 1 mmol) at 5 °C. The mixture
was stirred at r.t. for 18 h and the white precipitate formed was col-
lected by filtration. The precipitate was dried in vacuo to afford 5 as
colourless crystals (53 mg, 97%) in a diastereoisomeric ratio of 4:1
[determined by normal-phase HPLC: CHCl3–CH2Cl2, 95:5; flow
rate: 0.5 mL/min; minor diastereoisomer (19.25 min), major diaste-
reoisomer (25.77 min)].
IR (film): 1649, 1607, 1490, 1449 cm–1.
FABMS: m/z (%) = 461 (MNa+, 80), 439 (32), 176 (45).
HRMS: m/z calcd for C24H27N2O6 [MH+]: 439.1869; found:
(16) Garanti, L.; Sala, A.; Zecchi, G. J. Org. Chem. 1975, 40,
2403.
439.1850.
Synthesis 2005, No. 19, 3423–3427 © Thieme Stuttgart · New York