Nitrile oxide cycloaddition chemistry using benzotriazole as a steric auxiliary

Article abstract of DOI:10.1071/CH05189

The relatively hindered 2,2-bis(benzotriazol-1-yl)acetonitrile oxide was prepared in situ from the precursor hydroximinoyl chloride, and was allowed to react with dipolarophiles to give rise to several isoxazoles. The benzotriazole substituents acted as s

Full text of DOI:10.1071/CH05189

Full Paper
CSIRO PUBLISHING
www.publish.csiro.au/journals/ajc
Aust. J. Chem. 2005, 58, 877–881
Nitrile Oxide Cycloaddition Chemistry Using Benzotriazole
as a Steric Auxiliary
G. Paul SavageA,B and Gregory T. WernertA
A CSIRO Molecular and Health Technologies, Clayton South VIC 3169, Australia.
B Corresponding author. Email: paul.savage@csiro.au
The relatively hindered 2,2-bis(benzotriazol-1-yl)acetonitrile oxide was prepared in situ from the precursor hydrox-
iminoyl chloride, and was allowed to react with dipolarophiles to give rise to several isoxazoles. The benzotriazole
substituents acted as steric auxiliaries to prevent unwanted dimerization of the nitrile oxide to the furoxan by-product.
Manuscript received: 5 August 2005.
Final version: 30 September 2005.
Introduction
can occur in preference to dimerization, and this has been
attributed to the greater steric bulk of the substituent R, which
disfavours furoxan 2 formation. We have previously taken
advantage of this phenomenon by exploiting the steric bulk of
dithiane 4 to carry out cycloaddition reactions without com-
peting dimerization.[5] The dithiane 4 can be considered as a
masked analogue of propionitrile oxide, as the dithiane group
can be removed by desulfurization following cycloaddition.
In such cases, dimerization was repressed by the bulky
substituent, while cycloaddition reactions proceeded as
desired. The dithiane was thus shown to be a useful steric
auxiliary, albeit with limitations due to occasional prob-
lems associated with reaction at sulfur, and the modest
yield of preparation. In addition, desulfurization of the final
cycloadduct products to remove the steric auxiliary requires
relatively harsh conditions, which can lead to unwanted side
reactions.
The versatility of benzotriazole as a synthetic auxiliary
has been extensively exploited, and reviews by Katritzky
and co-workers attest to its prodigious synthetic utility.[6–8]
Benzotriazole is inexpensive, easy to install, and mildly elec-
tron withdrawing, but has the ability to donate electrons
depending on the nature of the substituent attached to the
nitrogen.[8] It is also straightforward to remove or substitute,
as the benzotriazolate anion is a reasonably stable leav-
ing group. It was this versatility that we chose to exploit
in an improved solution to the problem of dimerization of
The 1,3-dipolar cycloaddition reaction of nitrile oxides 1
with carbon dipolarophiles is a versatile and powerful syn-
thetic method to prepare ꢀ2-isoxazolines and isoxazoles,
which in turn, are useful precursors to β-hydroxy ketones,
β-amino alcohols, 1,3-diols, and a range of other 1,3-
disubstituted compounds.[1] Nitrile oxides also react with
themselves in 1,3-cycloadditions to give dimeric furoxan
products 2 (Scheme 1), and it is the comparative reactivity
of the intended dipolarophile and the nitrile oxide itself that
determines the extent of this competing side reaction.[2]
In general, alkylnitrile oxides are more prone to dimeriza-
tion than arylnitrile oxides. In particular, alkylnitrile oxides
with low degrees of substitution adjacent to the nitrile
oxide give modest yields of cycloadducts in reactions with
mono- and 1,1-disubstituted alkenes. When treated with
1,2-disubstituted and higher substituted alkenes, alkylnitrile
oxides generally undergo dimerization in preference to the
desired cycloaddition. This is the case even when the nitrile
oxide is generated in situ in the presence of an excess of the
alkene dipolarophile. The furoxans 2 formed by dimeriza-
tion do not necessarily represent a dead end in nitrile oxide
cycloadditionchemistry, however, asexamplesofthermolytic
cycloreversion to nitrile oxides and subsequent cycloaddi-
tion reactions have been reported.[3,4] Unfortunately, these
methods are not widely applicable because of the forcing
conditions required for the cycloreversion.
When the alkylnitrile oxide is highly substituted, such as
in 2,2-dimethylpropionitrile oxide 3 (Fig. 1), cycloaddition
ϩ
Ϫ
C
N
O
S
S
C
ϩ
N
Ϫ
O
R
R
ϩ
Ϫ
R
C
N
O
Nϩ
2
3
4
Ϫ
O
N
O
Fig. 1. The structures of 2,2-dimethylpropionitrile oxide 3 and
the dithiane 4, in which cycloaddition can occur in preference to
dimerization.
1
2
Scheme 1.
© CSIRO 2005
10.1071/CH05189
0004-9425/05/120877

878
G. P. Savage and G. T. Wernert
N
N
N
N
N
N
N
N
N
N
N
N
N
OH
OH
Benzotriazole
Toluene
1. BuLi
2. HCO CH
N
CH2
N
2
3
CH2Cl
5
6
7
N
N
N
N
N
N
N
N
N
N
OH
N
OH
H NOH·HCl
2
N-Chlorosuccinimide
Sodium acetate
water/ethanol
DMF/HCl (trace)
Cl
N
N
N
9
8
Scheme 2.
N
N
N
N
N
N
N
N
N
N
ϩ
N
Ϫ
O
Dipolarophile 11a–11g
O
KHCO
3
R1
9
N
N
N
R2
R3
10
12a–12g
Scheme 3.
nitrile oxides—by temporarily introducing bulky benzotria-
zole substituents as steric auxiliaries. As an additional bonus,
it was expected that the benzotriazole-substituted cycload-
dition products thus formed would be flexibly amenable to
further transformation if required.
were devoid of resonances typically associated with aldehy-
des. Treatment of the hydrate 7 with ethanol readily formed
a hemiacetal, which could also be isolated as a stable solid.
Aldehyde and ketone hydrates are commonly observed when
α-halogenated (compare chloral hydrate and hexafluoroace-
tone). In this case, the electron-withdrawing nature of the two
benzotriazole substituents probably stabilizes the hydrate 7,
relative to the corresponding aldehyde. The aldehyde
hydrate 7 was then treated with hydroxylamine hydrochloride
under standard conditions[14] to give the aldoxime derivative
8. Treatment of this aldoxime with N-chlorosuccinimide in
DMF, again under standard conditions,[15] gave the hydroxi-
moyl chloride 9 in high yield, as a stable white solid.
The cycloaddition precursor bis(benzotriazol-1-yl)-
acetonitrile oxide 10 was not isolated but rather generated
in situ by treating the hydroximoyl chloride 9 with potas-
sium bicarbonate in wet ethyl acetate, in the presence of
the appropriate substituted alkenes.[16] Cycloaddition took
place with a range of dipolarophile alkenes to give the
corresponding 3-[bis(benzotriazol-1-yl)methyl] substituted
ꢀ2-isoxazolines (Scheme 3). In keeping with the general
reactivity of nitrile oxides, the more highly substituted,
especially 1,2-disubstituted, dipolarophiles gave lower yields
compared to monosubstituted dipolarophiles. However, there
was still quite some variability in yield, presumably due to
competing steric and electronic effects.
Results and Discussion
The most convenient precursors to nitrile oxides are the
corresponding hydroximoyl chlorides, which eliminate HCl
upon treatment with mild bases such as triethylamine
and carbonate.[9] The synthesis of the bisbenzotriazole
hydroximoyl chloride 9 proceeded as follows (Scheme 2).
Bis(benzotriazol-1-yl)methane 6 was prepared by a modi-
fication of the procedures reported in the literature.[10–12]
Nucleophilic displacement of 1-chloromethylbenzotriazole 5
with an excess of the weakly acidic benzotriazole in hot
toluene gave bis(benzotriazol-1-yl)methane 6, along with a
trace of the corresponding benzotriazol-2-yl isomer. Benzo-
triazole is a mildly electron withdrawing substituent and,
hence, bis(benzotriazol-1-yl)methane can be deprotonated
with base. As such, treatment of 6 with butyllithium fol-
lowed by methyl formate led to 2,2-bis(benzotriazol-1-
yl)acetaldehyde, which was isolated as the stable hydrate 7.
The more usual formylating agent, dimethylformamide
(DMF), did not lead to the desired product, presumably
due to steric hindrance around the lithium bisbenzotria-
zole complex.[13] Evidence for hydrate formation included a
strong infrared absorption at 3250 cm−1 and a weak absorp-
tion at 1720 cm−1, while the 1H NMR and 13C NMR spectra
Nitrile oxide cycloaddition reactions with unsymmetrical
dipolarophiles can proceed to give a mixture of two
regioisomers, although with monosubstituted dipolarophiles
the product is usually exclusively the 5-substituted

Nitrile Oxide Cycloaddition Chemistry
879
N
N
N
N
Table 1. Cycloaddition reactions between nitrile oxide 10 and
selected dipolarophiles 11a–11g
N
N
N
N
O
O
NaBH4
Entry
Dipolarophile
11a–11g
Cycloadducts
12a–12gA
YieldB
[%]
H3C
Ph
Ph
O
N
OCOCH3
Bt
a
77
OCOCH3
12g
13
Bt
Scheme 4.
O
N
CO2CH3
CH3
Bt
b
c
70
61
reported.[19,20] By comparison, acetonitrile oxide itself has a
short half life, and the precursor acetohydroximinoyl chloride
is unstable.[21] It is expected that such mild removal of ben-
zotriazole would also proceed readily with other substituted
isoxazolines and isoxazoles. As benzotriazole substituents
can also be displaced by a variety of nucleophiles (such
as amines, Grignard reagents, thiolate anions),[22] the use
of benzotriazole-substituted acetonitrile oxide in dipolar
cycloadditionreactionsrepresentsahighlyversatilesynthesis
of substituted 3-methyl isoxazoles and ꢀ2-isoxazolines.
CH3
CO2CH3
Bt
O
N
Bt
CH3
H3C
CO2Et
Bt
CO2Et
O
N
Bt
Bt
Ph
Ph
d
e
CO2CH3
42
26
Bt
CO2CH3
O
N
Conclusions
Ph
Ph
Ph
Bis(benzotriazol-1-yl)acetonitrile oxide 10 is a convenient
synthon for acetonitrile oxide derivatives. It undergoes nitrile
oxide cycloaddition reactions without the common concomi-
tant problem of dimerization to furoxans. It will be possible
to elaborate the resulting bisbenzotriazolmethyl-isoxazoles
or -ꢀ2-isoxazolines to give a flexible range of isoxazole or
ꢀ2-isoxazoline derivatives.
Ph
Bt
O
N
Bt
f
51
48
Bt
O
N
Ph
Bt
g
Ph
C
HC
Experimental
Bt
Melting points were measured (uncorrected) on an Electrothermal appa-
ratus, and microanalyses were performed by the Campbell Microana-
lytical Laboratory, University of Otago. Infrared spectra were recorded
on a Perkin Elmer 783 instrument. 1H NMR spectra were recorded on a
Varian Gemini 200 MHz spectrometer or a Bruker WM 200 instrument
with SiMe4 as the internal standard. 13C NMR spectra were recorded on
a Varian Gemini 200 MHz spectrometer at 50.3 MHz. Low-resolution
mass spectra were obtained with a Finnigan 3300 instrument, or a JEOL
JMS-DX 303 instrument, as chemical ionization spectra with methane
as the reagent gas, or using APCI techniques on a Micromass LC/MS
platform. High-resolution mass spectra were recorded on a Micron-SS
77OF instrument or as electrospray (ES) on a Bruker BioApex FT mass
spectrometer.
A Bt = Benzotriazol-1-yl. B Isolated and purified yield.
isoxazolines.[1] In reactions with bis(benzotriazol-1-yl)-
acetonitrile oxide 10 (Table 1), only a single regioisomer was
detected for each case, except entries c and d where a trace of
another isomer (not isolated) was detected by gas chromatog-
raphy mass spectrometry (GC-MS). The regiochemistry of
the cycloaddition can be determined by NMR spectroscopy
of the product, as the chemical shift of the H4 protons on isox-
azolines is significantly upfield (approx. 1 ppm) from the H5
proton chemical shift.[17,18]
No evidence of dimerization to the furoxan could be
detected in any of these reactions. Indeed, the nitrile oxide 10,
generated in situ without the presence of a dipolarophile,
completely resisted dimerization. Even under forcing condi-
tions of heat or extended reaction periods, the nitrile oxide
started to break down hydrolytically rather than dimerize,
with benzotriazole being the only isolatable product.
The flexibility of using benzotriazole as a steric auxil-
iary was demonstrated by the ease of removal under mild
reducing conditions. Hence, when the bis(benzotriazol-1-
yl)methyl substituted isoxazole 12g was treated with sodium
borohydride in ethanol, the benzotriazole auxiliaries were
cleanly removed to give the corresponding methyl isoxa-
zole 13 (Scheme 4), which was identical to that previously
Column chromatography was carried out using silica gel 60 (Merck,
Art. 9385, 230-400#). Analytical thin-layer chromatography (TLC)
was performed on aluminium sheets precoated with silica 60 (Merck,
Art 5567). Spots were visualized with a UV lamp, iodine vapour,
bromocresol green solution, or with 2,4-dinitrophenylhydrazine.
1,1-Bis(benzotriazol-1-yl)methane 6
1-(Chloromethyl)benzotriazole 5 (20.10 g, 0.12 mol) was mixed with
benzotriazole (28.40 g, 0.24 mol) in toluene (200 mL) and the stirred
mixture was heated to reflux for 24 h during which time a white precip-
itate formed. The reaction mixture was cooled and the precipitate was
collected.The solid was triturated with hot water and recrystallized from
ethanol to yield 1,1-bis(benzotriazol-1-yl)methane 6 (20.7 g, 69%), mp
191–193◦C (lit.[9] 192–193◦C) as a white powder. δH 7.33–7.56 (m, 4H,
ArH), 7.42 (s, 2H, Bt2CH2), 7.86 (d, 2H, J 8, ArH), 8.03 (d, 2H, J 8,
ArH). δC 146.3, 132.1, 128.7, 124.8, 120.1, 109.8, 58.0. m/z 251 (10%,
MH+•), 132 (100), 118 (100).

880
G. P. Savage and G. T. Wernert
2,2-Bis(benzotriazol-1-yl)-1,1-dihydroxyethane 7
Cycloaddition Reactions Between Alkenes a–f and Bis(benzotriazol-
1-yl)acetonitrile Oxide 10, Generated In Situ from 2,2-
A solution of the bisbenzotriazolemethane 6 (6.25 g, 25 mmol) in anhy-
drous tetrahydrofuran (200 mL) was stirred under argon and cooled to
–70◦C (dry ice/ethanol). n-Butyllithium in hexane (1.6 M, 17.5 mL,
28 mmol) was added dropwise. During the addition, a dark coloured
solution developed. The mixture was stirred at −70◦C for 1.5 h after
which time methyl formate (1.64 g, 27 mmol) in anhydrous tetrahydro-
furan (30 mL) was added dropwise. The mixture was stirred at −70◦C
for 2 h, allowed to warm to room temperature, and then stirred for a
further 16 h. The reaction mixture was treated with saturated aqueous
ammonium chloride (50 mL) and the mixture was extracted with diethyl
ether (3 × 50 mL). The combined organic phases were dried (MgSO4),
filtered, and concentrated under reduced pressure to yield a white glassy
solid (6.5 g). This material was subjected to flash column chromatog-
raphy (silica, 1/4 dichloromethane/ethyl acetate elution) to afford a
waxy solid. Recrystallization (acetone/hexane) afforded the dihydrox-
yethane 7 (2.52 g, 34%) as a white powder, mp 143.5–147.5◦C. (Found:
[M + Na]+ 319.091. C14H12N6O2Na requires [M + Na]+ 319.092.)
νmax (KBr)/cm−1 3600–2450br, 1750–1710br, 1625, 1600, 1505, 1460,
1320, 1300, 1250, 1180s, 1150–1080, 960, 850, 840, 800, 790, 760. δH
6.70 (q, 1H, J 7, Bt2CHCH(OH)2), 7.10 (d, 2H, J 6, Bt2CHCH(OH)2,
exchangeable with D2O), 7.45 (t, 2H, J 7, ArH), 7.65 (t, 2H, J 7, ArH),
7.75 (d, 1H, J 7.5, Bt2CHCH(OH)2), 8.12 (d, 2H, J 8,ArH), 8.25 (d, 2H, J
8,ArH). δC 145.1, 132.7, 128.5, 124.8, 119.5, 111.0, 88.0, 72.9. m/z 279
(18%, [MH − H2O]+), 249 (76), 221 (30), 160 (100), 132 (55), 120 (20).
Bis(benzotriazol-1-yl)-1-chloro-1-(hydroxyimino)ethane 9
To a solution of 2,2-bis(benzotriazol-1-yl)-1-chloro-1-(hydroxyimino)-
ethane 9 (328 mg, 1 mmol) in ethyl acetate (10 mL) was added the
appropriate alkene 11a–11f (1.1 mmol). Potassium bicarbonate (1 g)
was added followed by water (2–3 drops) and the mixture was stirred at
room temperature for 16 h.The mixture was filtered to remove insoluble
solids. The solids were washed with dichloromethane and the combined
washings and ethyl acetate filtrate were concentrated under reduced
pressure.The residue was partitioned between dichloromethane (40 mL)
and water (40 mL), and the dichloromethane was separated and retained.
The aqueous layer was extracted with dichloromethane (2 × 30 mL)
and the combined organic layers were dried (Na2SO4), filtered, and
concentrated under reduced pressure to yield the crude product.
3-[Bis(benzotriazol-1-yl)methyl]-∆2-isoxazolin-5-ylmethyl
Acetate 12a
The crude material was purified by column chromatography (silica,
dichloromethane/ethyl acetate, 9/1) to yield the ∆2-isoxazoline acetate
12a as a white glassy solid (300 mg, 77%). (Found: C 58.2, H 4.3,
N25.2%;MH+• 392.148. C19H17N7O3 requiresC58.3, H4.4, N25.1%;
MH+• 392.147.) δH 2.09 (s, 3H, COCH3), 3.28 (dd, 1H, J 18, 7, isox.
H4), 3.54 (dd, 1H, J 18, 10, isox. H4), 4.21–4.39 (m, 2H, CH2OCOMe),
5.08–5.20 (m, 1H, isox. H5), 7.32–7.52 (m, 4H, ArH), 7.58 (d, 2H,
J 10, ArH), 8.03 (d, 2H, J 10, ArH), 8.60 (s, 1H, Bt2CH). δC 170.8,
151.7, 146.3, 131.9, 129.1, 125.2, 120.4, 110.1, 80.3, 67.8, 64.5, 37.7,
20.7. m/z 392 (10%, MH+•), 364 (12), 336 (25), 273 (100), 247 (93),
185 (87), 148 (81), 120 (53).
2,2-Bis(benzotriazol-1-yl)-1-(hydroxyimino)ethane 8
The dihydroxyethane 7 (6.16 g, 19 mmol) was mixed with hydroxy-
lamine hydrochloride (2.64 g, 38 mmol) and sodium acetate trihydrate
(5.17 g, 38 mmol) in water (75 mL). Ethanol (90 mL) was added to the
stirred suspension. The mixture was heated to 75◦C for 5 h after which
time the mixture was concentrated under reduced pressure. The result-
ing solid was partitioned between dichloromethane (100 mL) and water
(100 mL), and the dichloromethane was separated and retained. The
aqueous layer was extracted with dichloromethane (2 × 70 mL) and the
combined organic layers were dried (Na2SO4), filtered, and concen-
trated under reduced pressure to yield a glassy solid. Trituration with
hot hexane yielded the oxime 8 as an unseparated mixture of E- and Z-
isomers (5.17 g, 93%) as a white powder, mp 89–93◦C. (Found: C 57.4,
H 3.5, N 33.3%; M+• 293.102. C14H11N7O requires C 57.3, H 3.8,
N 33.4%; M+• 293.103.) δH 7.32–7.55 (m, 4H, ArH), 7.89 (d, 2H, J
8, ArH), 7.93–8.00 (m, 2H, ArH), 8.38 (d, 1H, J 2, Bt2CHCH=NOH),
8.76 (d, 0.05H, J 2, Bt2CHCH=NOH, isomer 1) and 8.88 (d, 0.95H,
J 2, Bt2CHCH=NOH, isomer 2). δC 145.8, 145.7, 141.6, 139.7, 131.5,
128.9, 125.1, 120.0, 110.1, 110.0, 69.3, 63.3. m/z 293 (7%, M+•), 175
(100), 120 (52), 104 (37), 93 (35).
Methyl 3-[Bis(benzotriazol-1-yl)methyl]-5-methyl-∆2-isoxazoline-5-
carboxylate 12b
The crude material was purified by column chromatography (silica,
dichloromethane/ethyl acetate, 9/1) to yield the ∆2-isoxazoline car-
boxylate 12b as a white glassy solid (271 mg, 70%). (Found: C 58.5,
H 4.4, N 25.2%; [M + Na]+ 414.129. C19H17N7O3 requires C 58.3, H
4.4, N 25.1%; [M + Na]+ 414.129.) δH 1.76 (s, 3H, isox. 5-CH3), 3.38
(d, 1H, J 17, isox. H4), 3.79 (s, 3H, OCH3), 3.85 (d, 1H, J 17, isox. H4),
7.30–7.51 (m, 4H, ArH), 7.59–7.64 (m, 2H, ArH), 8.00–8.06 (m, 2H,
ArH), 8.57 (s, 1H, Bt2CH). δC 171.7, 151.9, 146.3, 132.0, 129.2, 125.3,
120.6, 110.2, 88.3, 67.9, 53.5, 45.4, 23.6. m/z 414 (32%, [M + Na]+),
392 (26%, M+•), 273 (100), 139 (55), 120 (45).
Ethyl 3-[Bis(benzotriazol-1-yl)methyl]-5-methyl-∆2-isoxazoline-4-
carboxylate 12c
The crude material was purified by column chromatography (silica,
dichloromethane/ethyl acetate, 9/1) to yield the ∆2-isoxazoline car-
boxylate 12c as a glassy solid (247 mg, 61%). (Found: C 59.5, H 4.6,
N 24.3%; [M + Na]+ 428.145. C20H19N7O3 requires C 59.3, H 4.7,
N 24.2%; [M + Na]+ 428.145.) δH 1.09 (t, 3H, J 8, OCH2CH3), 1.64
(d, 3H, J 6.5, isox. 5-CH3), 3.98–4.65 (m, 2H, OCH2CH3), 4.20 (d,
1H, J 8, isox. H4), 5.14–5.28 (m, 1H, isox. H5), 7.26–7.63 (m, 4H,
ArH), 7.73–7.78 (m, 2H, ArH), 7.95–8.06 (m, 2H, ArH), 8.93 (s, 1H,
Bt2CH). δC 171.7, 148.8, 146.5, 132.3, 129.3, 125.4, 120.7, 110.7, 82.8,
67.7, 62.7, 59.4, 20.5, 14.0. m/z 405 (100%, M+•), 348 (44), 332 (30),
304 (70), 302 (95), 274 (30).
2,2-Bis(benzotriazol-1-yl)-1-chloro-1-(hydroxyimino)-ethane 9
A stirred solution of the oxime 8 (1.46 g, 5 mmol) in dimethylformamide
(6 mL) was maintained under argon. N-Chlorosuccinimide (136 mg,
0.75 mmol) was added followed by HCl gas (5 mL) by syringe to cat-
alyze the reaction. The HCl gas was obtained from the head-space of a
reagent bottle of concentrated hydrochloric acid. The reaction mixture
was warmed to 35◦C and N-chlorosuccinimide (770 mg, 4.25 mmol)
was added as several portions, the reaction temperature being main-
tained at 35◦C during the addition. The reaction mixture was allowed
to cool to room temperature where it was maintained for 16 h and then
added to ice/water (80 mL). An off-white precipitate formed which was
collected and washed with water. The solid was triturated with water
to yield the title compound 9 as a white powder (1.64 g, 100%). An
analytical sample was crystallized from ethyl acetate/hexane to yield
colourless crystals, mp 127.5–128.5◦C (dec.). (Found: C 51.6, H 3.0,
Cl 10.7, N 29.7%. C14H10ClN7O requires C 51.3, H 3.1, Cl 10.8,
N 29.9%.) δH 7.20 (t, 2H, J 6, ArH), 7.34 (t, 2H, J 6, ArH), 7.65 (d, 2H,
J 10, ArH), 7.86 (d, 2H, J 10, ArH), 8.61 (s, 1H, Bt2CHC(Cl)=NOH),
12.35 (s, 1H, NOH). δC 146.0, 132.6, 130.5, 129.3, 125.5, 120.2,
111.1, 72.6.
Methyl 3-[Bis(benzotriazol-1-yl)methyl]-5-phenyl-∆2-isoxazoline-4-
carboxylate 12d
The crude material was purified by column chromatography (silica,
dichloromethane/ethyl acetate, 9/1) to give a less polar fraction of unre-
acted methyl cinnamate and a more polar fraction of the ∆2-isoxazoline
carboxylate 12d as a glassy solid (190 mg, 42%). (Found: C 63.4, H
4.1, N 21.2%; [M + Na]+ 476.144. C24H19N7O3 requires C 63.6, H
4.2, N 21.6%; [M + Na]+ 476.145.) δH 3.65 (s, 3H, OCH3), 4.64 (d,
1H, J 10, isox. H4), 6.12 (d, 1H, isox. J 10, H5), 7.3–7.6 (m, 9H, ArH),
7.81 (t, 2H, J 8, ArH), 8.02 (d, 1H, J 8, ArH), 8.03 (d, 1H, J 8, ArH),

Nitrile Oxide Cycloaddition Chemistry
881
8.95 (s, 1H, Bt2CH). δC 167.5, 148.1, 146.7, 138.1, 132.3, 131.7, 129.3,
129.2, 128.6, 125.3, 120.1, 111.9, 87.3, 67.9, 60.6, 53.5. m/z 452 (68%,
M
with diethyl ether. The combined organic layers were dried (MgSO4),
filtered, and concentrated under reduced pressure. The residue was puri-
fied by column chromatography with hexane/EtOAc (2/1) as an eluent
to give the title compound as a white solid, mp 65◦C (lit.[20] 65◦C).
δH 7.72 (d, 2H, ArH), 7.41 (m, 3H, ArH), 6.46 (s, 1H, CH), 2.35 (s, 3H,
CH3). δC 157.9, 148.0, 136.4, 129.0, 128.0, 126.3, 98.4, 15.3.
+•), 274 (26), 118 (100).
3-[Bis(benzotriazol-1-yl)methyl]-5,5-diphenyl-∆2-isoxazoline 12e
The crude material was purified by column chromatography (silica,
dichloromethane/ethyl acetate, 9/1) to give the ∆2-isoxazoline 12e as a
white powder (122 mg, 26%), mp 205–207.5◦C. (Found: C 71.2, H 4.2,
N 20.7%; [M + Na]+ 494.170. C28H21N7O requires C 71.3, H 4.5,
N 20.8%; [M + Na]+ 494.171.) νmax (KBr)/cm−1 3441br, 3066, 1613,
1593, 1493, 1450, 1359, 1291, 1279, 1158, 1109, 1004, 928, 915. δH 4.05
(s, 2H, isox. H4), 7.30–7.50 (m, 14H, ArH), 7.65 (d, 2H, J 8, ArH), 8.00
(d, 2H, J 8, ArH), 8.57 (s, 1H, Bt2CH). δC 151.4, 146.2, 142.8, 131.8,
128.9 (two overlapping signals), 128.1, 126.0, 125.0, 120.3, 110.3, 94.5,
67.9, 48.5. m/z 494 (32%, [M + Na]+), 353 (45).
References
[1] C. J. Easton, C. M. M. Hughes, G. P. Savage, G. W. Simpson, Adv.
Heterocycl. Chem. 1994, 60, 261.
[2] D. P. Curran, S. A. Scanga, C. J. Fenk, J. Org. Chem. 1984, 49,
3474. doi:10.1021/JO00193A008
[3] D. P. Curran, C. J. Fenk, J. Am. Chem. Soc. 1985, 107, 6023.
doi:10.1021/JA00307A031
[4] T. Shimizu, Y. Hayashi, K. Teramura, J. Org. Chem. 1983, 48,
3053. doi:10.1021/JO00166A024
3-[Bis(benzotriazol-1-yl)methyl]-1,2-oxazaspiro[4,5]-dec-2-ene 12f
[5] S. J. Barrow, C. J. Easton, G. P. Savage, G. W. Simpson, Tetrahe-
dron Lett. 1997, 38, 2175. doi:10.1016/S0040-4039(97)00275-X
[6] A. R. Katritzky, J. Heterocycl. Chem. 1999, 36, 1501.
[7] A. R. Katritzky, S. A. Belyakov, Aldrichchimica Acta 1998,
31, 35.
[8] A. R. Katritzky, X. Lan, J. Z. Yang, O. V. Denisko, Chem. Rev.
1998, 98, 409. doi:10.1021/CR941170V
[9] A. Werner, H. Buss, Chem. Ber. 1894, 27, 2193.
[10] J. H. Burckhalter, V. C. Stevens, L. A. R. Hall, J. Am. Chem. Soc.
1952, 74, 3868. doi:10.1021/JA01135A044
The crude material was purified by column chromatography (silica gel,
dichloromethane/ethyl acetate, 9/1) to yield the oxazaspiro[4,5]-dec-
2-ene 12f as a white powder (196 mg, 51%), mp 180–182◦C. (Found:
C 65.4, H 5.3, N 25.5%; [M + Na]+ 410.170. C21H21N7O requires
C 65.1, H 5.5, N 25.3%; [M + Na]+ 410.171.) δH 1.32–1.60 (br m,
6H, cyclohexyl), 1.60–2.02 (m, 4H, cyclohexyl), 3.09 (s, 2H, isox. H4),
7.32–7.49 (m, 4H, ArH), 7.63 (d, 2H, J 8, ArH), 8.03 (d, 2H, J 8, ArH),
8.51 (s, 1H, Bt2CH). δC 150.9, 146.2, 131.9, 128.9, 125.0, 120.2, 110.3,
90.2, 68.2, 45.3, 36.2, 24.8, 23.2. m/z 410 (100%, [M + Na]+).
[11] A. R. Katritzky, D. Toader, J. Am. Chem. Soc. 1997, 119, 9321.
doi:10.1021/JA972037Y
[12] A. R. Katritzky, D. Toader, L. Xie, J. Org. Chem. 1996, 61, 7571.
doi:10.1021/JO960841H
[13] A. R. Katritzky, Z. Yang, J. Lam, J. Org. Chem. 1991, 56, 2143.
doi:10.1021/JO00006A034
[14] E. Wenkert, B. S. Bernstein, J. H. Udelhofen, J. Am. Chem. Soc.
1958, 80, 4899. doi:10.1021/JA01551A034
3-[Bis(benzotriazol-1-yl)methyl]-5-phenylisoxazole 12g
To a solution of the chlorooxime 9 (327 mg, 1 mmol) in ethyl acetate
(10 mL) containing phenylacetylene (150 mg, 1.5 mmol) was added
potassium bicarbonate (1 g, 10 mmol) followed by water (2–3 drops).
The mixture was stirred at room temperature for 16 h and then filtered,
the filtrate was dried (MgSO4), filtered, and concentrated under reduced
pressure to yield a brown viscous oil (400 mg). The crude material
was purified by column chromatography (silica, dichloromethane/ethyl
acetate, 9/1) to give a light-brown semi-solid, which recrystallized
from acetone/hexane to give the phenylisoxazole 12g as fluffy nee-
dles (190 mg, 48%), mp 146–148◦C. (Found: C 67.4, H 3.6, N 24.8%;
[M + Na]+ 416.124. C22H15N7O requires C 67.2, H 3.8, N 24.9%;
[M + Na]+ 416.124.) δH 6.86 (s, 1H, isox. H4), 7.36–7.55 (m, 7H,ArH),
7.78–7.82 (m, 4H, ArH), 8.06 (d, 2H, J 8, ArH), 9.01 (s, 1H, Bt2CH).
δC 172.0, 157.9, 146.4, 132.0, 131.0, 129.2, 129.1, 126.5, 126.1, 125.1,
120.5, 110.4, 99.9, 66.8. m/z 393 (20%, M+•), 336 (100), 144 (55),
118 (100).
[15] K.-C. Liu, B. R. Shelton, R. K. Howe, J. Org. Chem. 1980, 45,
3916. doi:10.1021/JO01307A039
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K. B. G. Torssel, Acta Chem. Scand. A 1993, 47, 1004.
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M. F. Mackay, Aust. J. Chem. 1993, 46, 1401.
[19] Y. Basel, A. Hassner, Synthesis 1997, 309. doi:10.1055/S-1997-
1181
[20] G. Bianchi, P. Gruenanger, Tetrahedron 1965, 21, 817.
doi:10.1016/0040-4020(65)80014-X
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47, 2683. doi:10.1016/S0040-4020(01)87080-0
3-Methyl-5-phenyl Isoxazole 13
A mixture of the phenylisoxazole 12g (394 mg, 1 mmol) and NaBH4
(160 mg, 4 mmol) was stirred in anhydrous ethanol (15 mL) at 25◦C
overnight. The reaction mixture was quenched with water and extracted