Chiral ruthenium Lewis acid-catalyzed nitrile oxide cycloadditions

Article abstract of DOI:10.1016/j.tet.2007.06.033

The synthesis of the chiral ligand (R,R)-BIPHOP-F is detailed. Its coordination to a cationic cyclopentadienyl ruthenium fragment generates [Ru (acetone)(R,R)-BIPHOP-F)Cp][SbF₆], a transition metal Lewis acid that catalyzes the [3+2] dipolar cy

Full text of DOI:10.1016/j.tet.2007.06.033

Tetrahedron 63 (2007) 8413–8419
Chiral ruthenium Lewis acid-catalyzed nitrile oxide
cycloadditions
Yasmin Brinkmann,a Reniguntala J. Madhushaw,a Rodolphe Jazzar,a
b
Gerald Bernardinelli and E. Peter Kundig
a,
*
€
aDepartment of Organic Chemistry, University of Geneva, 30 Quai Ernest-Ansermet, CH-1211 Geneva 4, Switzerland
bLaboratory of Crystallography, University of Geneva, 24 Quai Ernest-Ansermet, CH-1211 Geneva 4, Switzerland
Received 30 April 2007; revised 7 June 2007; accepted 12 June 2007
Available online 16 June 2007
Abstract—The synthesis of the chiral ligand (R,R)-BIPHOP-F is detailed. Its coordination to a cationic cyclopentadienyl ruthenium fragment
generates [Ru (acetone)(R,R)-BIPHOP-F)Cp][SbF6], a transition metal Lewis acid that catalyzes the [3+2] dipolar cycloaddition reaction
between aryl nitrile oxides and a,b-unsaturated aldehydes to give chiral 2-isoxazolines with yields of 43–98% and asymmetric purity of
60–93% ee. The stereochemistry of the major enantiomer is S, consistent with an approach of the nitrile oxide to the Ca-Si face of the
enal in the anti-s-trans conformation in the catalyst site.
Ó 2007 Elsevier Ltd. All rights reserved.
Ukaji and Inomata7c
:
1. Introduction
CO2i-Pr
i-PrO2C
1.
Chiral, enantiopure 2-isoxazolines are important heterocy-
cles and several members of this family of compounds
exhibit significant biological activity.1 They are also pre-
cursors to useful chiral acyclic building blocks such as
b-hydroxy ketones2 and g-aminoalcohols.3 A convenient
one-step route of access to 2-isoxazolines4 is by 1,3-dipolar
cycloaddition reaction of nitrile oxides5 with alkenes, albeit
that the tendency of nitrile oxides to dimerize severely com-
plicates matters.
HO
(0.2 eq.)
OH
O
N
OH
OH
Et Zn (1.7 eq.)
2.
3.
2
R
ArC(Cl)NOH (2.5 eq.)
dioxane (1.5 eq.)
CHCl3, 18-20 h, 0 °C
R=Ar, tBu
90-98%, 90-93% ee
O
O
Sibi7d
:
N
N
O
MgI2
(0.3 eq.)
O
O
N
For chiral non-racemic 2-isoxazolines diastereoselective
[3+2] cycloadditions have been developed successfully6
but enantioselective variants remain scarce (Scheme 1).7,8
Ukaji and co-workers reported the reaction of nitrile oxides
with an allylic alcohol in the presence of an in situ generated
chiral Lewis acid derived from ZnCl2 and diisopropyltar-
trate.7 More recently, Sibi and co-workers used a chiral Lewis
acid prepared from magnesium iodide and a chiral bisoxazo-
line derived from a 1,2-amino indanol.8 This catalyst requires
a chelating substrate and the best dienophiles were those in-
corporating a pyrazolidinone. While these results are impres-
sive, we note that catalyst loading is high and that an
extension of the methods for this reaction type would be use-
ful. Both reported reactions likely involve two-point binding
of the dienophile to the Lewis acid and in Sibi’s example, this
requires the introduction and removal of an auxiliary group.
+
N
BnN
CH2Cl2, rt, MS 4A
2.5 h
O
O
NaBH4
CH2OH
N
N
O
O
N
N
84%, 99% ee
Scheme 1. Two examples of chiral Lewis acid-catalyzed cycloaddition
reactions of nitrile oxides with alkenes.
Over the past years we have developed one-point binding
chiral cationic cyclopentadienyl-FeL* and -RuL* catalysts
with well defined coordination spheres and have applied
these successfully to Diels–Alder reactions of dienes with
a,b-unsaturated aldehydes,9 and with a,b-unsaturated
ketones.10 Particular relevant to the work described in this
article is that the same catalysts were also successful in
* Corresponding author. Tel.: +41 22 379 6093; fax: +41 22 379 3215;
e-mail: peter.kundig@chiorg.unige.ch
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.06.033

8414
Y. Brinkmann et al. / Tetrahedron 63 (2007) 8413–8419
asymmetric [3+2] cycloaddition reactions between enals and
nitrones.11 Ease of generation of the Ru catalysts, stability in
solution at ambient temperature, high enantioselectivity in
Diels–Alder reactions, efficient catalyst recovery, and large
rate differences on variation of the anion are characteristics
of these Lewis acids.
Ligand 5 was then used to assemble the catalyst precursor as
detailed in Scheme 4.
Ph
Ph
OP(C6F5)2 1. Ru3CO12, CpH,
heptane, reflux, 2h
Ru
(C6F5)2P
O
I
2. CHI3, acetone, reflux, 24h
70% (2 steps)
P(C6F5)2
O
OP(C6F5)2
(R,R)-(+)-5
The Fe complexes have higher turnover rates but are ther-
mally less stable and cannot be recovered after the reaction.
Other arene and cyclopentadienyl half-sandwich complexes
have also been used as catalysts in the reactions of enals with
dienes and/or of enals with nitrones by the groups of
Davies,12 Carmona and Oro,13 and Faller.14 Different chiral
one-point binding Lewis acid catalysts for nitrone/enal
cycloadditions have recently emerged.15 Also, MacMillan
has reported a successful organocatalytic approach.16 How-
ever, at the time of writing, none of these catalysts have been
tested on nitrile oxide cycloaddition reactions. We here re-
port our results in this reaction using as catalyst precursor
the complex [Ru(acetone)(R,R)-BIPHOP-F)(Cp)][SbF6]. A
major concern for this reaction was the high donor ability
of the oxygen atom of the dipole.17 Irreversible nitrile oxide
binding would preclude asymmetric catalysis. A parallel
situation exists in the reactions of nitrones. Since we have
demonstrated reversibility of nitrone coordination to the
Lewis acid [Ru(BIPHOP-F)Cp]+,11 the hypothesis of a simi-
lar situation with nitrile oxides (Scheme 2) was worth test-
ing. The results reported here bear this out.
Ph
Ph
(R,R)- 6
-
SbF6
AgSbF6 (2 eq.),
acetone, 1.5h, rt
Ru
(C6F5)2P
O
O
P(C6F5)2
99%
O
Ph
Ph
(R,R)- 7
Scheme 4. Synthesis of [Ru(acetone)(R,R)-BIPHOP-F)Cp][SbF6]
((R,R)-7).
2.2. Synthesis of nitrile oxides
Initial studies were carried out with the stable mesityl nitrile
oxide 8a.18 As other nitrile oxides dimerize rapidly,8 they
were generated directly prior to use by treatment of the ap-
propriate hydroximoylchlorides with the resin Amberlyst
21. The requisite hydroximoylchlorides were obtained in
two steps from commercially available aldehydes.19
2.3. Cycloaddition reactions
H
-
SbF6
H
-
SbF6
N
O
The [3+2] cycloaddition reaction between mesityl nitrile ox-
ide (8a) and methacrolein (9) in methylene chloride at rt af-
forded 2-isoxazoline 10a in 90% yield (Table 1, entry 1). In
the presence of catalyst (R,R)-7 (5 mol %), an almost quan-
titative yield of 10a was obtained at 5 ꢀC after 12 h. Asym-
metric induction, measured by chiral HPLC after reduction
to 12a was, however, low (30% ee, entry 2). Lowering the
reaction temperature to ꢁ10 ꢀC did not improve the ee (entry
3). Thus, either catalyst 7 was not capable of providing better
asymmetric induction or the background reaction was im-
portant. To test for the latter, the nitrile oxide was added
via a syringe pump over a time period of 10 h to a solution
of 9 and catalyst 7 in CH2Cl2 at ꢁ15 ꢀC. This gave a 75%
yield of 10a with 60% ee (entry 4). In the next reaction
both 8a and 9 were added slowly (10 h) to the reaction mix-
ture. While the level of induction was nearly as high as for
entry 4, the acetal 11a formed as side product. Compound
11a results from the reaction of the isoxazoline aldehyde
Ru
(C6F )
5 2 P
Ru
O
(C6F )
5 2 P
O
6
O
P(C6F5)2
(C F )
P
O
O
5 2
O
O
N
Scheme 2. Reversible coordination of nitrile oxide and enal to the catalyst.
2. Results and discussion
2.1. Ligand and catalyst synthesis
The crystalline, air-stable ligand (R,R)-BIPHOP-F (5) was
synthesized as shown in Scheme 3.
F
F
Br
MgBr
F
P
F
F
1. Mg (3.5 eq.),
Et2O, reflux
PCl3 (1 eq.),
Et2O, 0 °C
Table 1. Cycloaddition reactions of mesityl nitrile oxide (8a) and methacro-
lein (9) in the presence of catalyst (R,R)-7
F
F
F
F
F
F
F
F
F
Br
F
2. rt, 18h
60%
Entry Time [h] T [ꢀC] 10a, yielda [%], eeb [%] 11a, yielda [%]
F
3
F
1
F
2
1
2
18
12
24
72
17
23
5
ꢁ10
ꢁ15
5
90, 0c
98, 30
89, 30
75, 60
60, 58
—
—
—
Traces
30
F
F
1. NEt3 (2.4 eq.)
3
4d
5e
2. BrP(C6F5)2 (2.2 eq.)
THF, rt, 24h
OH
OH
OP(C6F5)2
OP(C6F5)2
Ph
Ph
Ph
Ph
95%
a
b
c
d
e
Isolated yield.
(R,R) (1 eq)
Determined by chiral HPLC.
Without catalyst 7.
Slow addition of mesityl nitrile oxide (10 h).
(R,R)-BIPHOP-F ((R,R)-5)
4
Scheme 3. Synthesis of (R,R)-5.
Slow addition of mesityl nitrile oxide and methacrolein (10 h).

Y. Brinkmann et al. / Tetrahedron 63 (2007) 8413–8419
8415
Table 2. Cycloaddition reactions of nitrile oxides (8b–g, slow addition) and
methacrolein (9) in the presence of catalyst (R,R)-7
10a with a second molecule of 8a (entry 5). Further experi-
ments confirmed that more than 1 equiv of nitrile oxide leads
to increasing amounts of 11a to be formed and that an excess
of aldehyde results in an erosion of product enantioselectiv-
ity due to the uncatalyzed background reaction. High dilu-
tion diminished ee values as well.
Entry Nitrile oxide Time [h], temp [ꢀC] 12b–g, yielda [%], eeb [%]
1
2
8b, R¼Me
25, ꢁ5
51
65
57
71
58
60
61
43
66
63
65
63
76
93
76
74
8c, R¼i-Pr 38, ꢁ5
8d, R¼OMe 39, ꢁ5
8d, R¼OMe 17, ꢁ5
8e, R¼CF3 22, ꢁ5
8e, R¼CF3 16, ꢁ20
3
4c
5
6d
7
N
H
O
8f, R¼F
47, ꢁ5
24,e ꢁ5
Me
O
N
O
H1
O
8
8g, R¼Cl
Isolated yield.
-
O
O
N
O
(R,R)-7
+N
+
a
5 mol%
H
b
Determined by chiral HPLC. The S configuration is assigned to the major
enantiomer.
1 mmol scale, slightly higher dilution.
Slow addition of both nitrile oxide and methacrolein (10 h).
Reaction incomplete, crystallization of nitrile oxide at syringe pump
needle tip.
CH2Cl2
time, temp
+
1.5 eq.
9
c
d
e
8a
11a
10a
NaBH4, THF/H2O, 0 °C
HO
O-
(R,R)-7 (5 mol%)
CH2Cl2, -5 °C
N
O
O
+N
+
O
R
12a
H
H
R
N
O
1.5 eq
9
1 eq
8b-g
In the following, the study was extended to other aromatic
nitrile oxides bearing electron-donating and electron-with-
drawing substituents on the aromatic ring. All nitrile oxides
were generated in situ immediately prior to use. Racemic
cycloadducts 10b–g were prepared by reaction of nitrile
oxides 8b–g with methacrolein in CH2Cl2 at rt, followed
by reduction to give the alcohol derivatives (12b–g). In all
cases reactions afforded the 3,5-substituted isoxazolines as
single regioisomers.
10b-g
NaBH4
THF/H2O, 0 °C
R
HO
N
O
12b-g
Lowering the temperature to ꢁ20 ꢀC led to very inefficient
reactions for substrates with electron-rich arenes. With elec-
tron-withdrawing substituents, product ee’s (12e–g) in-
creased slightly (by 2–3%). However, simultaneous slow
addition of the reaction partners was beneficial in the case
of R¼CF3 (entry 6).
Tentative assignment of the structure was made based on
NMR data. As shown in Figure 1 this was confirmed for iso-
xazoline 12g by an X-ray structure determination.20
Asymmetric reactions were carried out by slow addition
(10 h) of the nitrile oxides to the CH2Cl2 solutions of meth-
acrolein and catalyst ((R,R)-7 (5%) at ꢁ5 ꢀC, Table 2).
Nitrile oxides with electron-withdrawing substituents in
the 4-position on the aromatic ring gave higher ees (entries
5–8) than those having electron-donating substituents (en-
tries 1–4). Yields are lower than for mesityl nitrile oxide
because dimerization of the substrates could not be avoided.
As a result, small quantities of furoxans, the products of
nitrile oxide dimerization, were also formed. Under the con-
ditions used, formation of the double addition products
11b–g could be avoided. Reaction times are not optimized
for entries 7 and 8. The reactivity of the tested substrates dif-
fers considerably and the reaction cannot easily be followed
by TLC, which complicates optimization.
2.4. Absolute configuration
Attempts to obtain an X-ray crystal structure of enantiomeri-
cally enriched 12g have not met with success. Therefore the
assignment of the absolute configuration is based on com-
parison of the optical rotation of 5-methyl-3-phenyl-4,5-
dihydro-isoxazole-carboxylic acid 13 with the literature
data. Compound 13 was obtained by oxidation of (5-meth-
yl-3-phenyl-4,5-dihydro-isoxazol-5-yl)methanol 12h (60%
ee) with trichloroisocyanuric acid in the presence of cata-
lytic amounts of TEMPO21 (Scheme 5). Compound 12h
was synthesized by asymmetric [3+2] cycloaddition cata-
lyzed by (R,R)-7 like compounds 12b–g. Compound 13
has an [a]2D5 +35 (c 0.48, CHCl3). For enantiopure (R)-13
an [a]2D5 ꢁ131 is reported.22 Consequently the stereogenic
center of the mayor enantiomer is assigned to be S. This
also ties in with a separate literature report, including CD
data, on enantiomerically enriched (S)-13.23
The assigned stereochemistry is in agreement with our pro-
posed model based on the X-ray structure of [Ru ((S,S)-BI-
PHOP-F)Cp(methacrolein)][SbF6].9 As (R,R)-BIPHOP (5)
was used in the present study, we show in Figure 2 the enan-
tiomeric structure of the data published earlier.9 Methacro-
lein is bound to (R,R)-7 in the anti-s-trans conformation
Figure 1. X-ray structure of rac-12g.

8416
Y. Brinkmann et al. / Tetrahedron 63 (2007) 8413–8419
Cl
N
N
gun for ca. 5 min. Purification of THF, diethyl ether, n-hex-
O
O
ane, toluene, and dichloromethane were carried out using
a SolvtekÓ purification system. Commercial chemicals
were used as supplied unless otherwise stated. Flash column
N
Cl
Cl
O
O
S
HO
HO
TEMPO, NaBr
˚
N
O
chromatography was carried out using silica gel (60 A/32–
N
13
O
O
NaHCO3 aq
,
63 mesh, Brunschwig SA, Basel). Thin layer chromato-
graphy was performed on pre-coated aluminum plates
(Merck silica 60F254) and visualized using UV light and
ethanolic phosphomolybdic acid.
12h ( 60% ee)
( [α]D25= +35; c 0.48, CHCl3)
Scheme 5. Synthesis of carboxylic acid 13.
1H, 31P, 19F, and 13C NMR spectra were recorded on Bruker
AMX 200, 300, 400, and 500 spectrometers. Chemical shifts
are quoted in parts per million relative to TMS, with cou-
pling constants quoted in hertz. Infrared spectra were re-
corded on a Perkin–Elmer spectrometer as neat liquids
using a Golden GateÓ accessory. Polarimetry was performed
with a Perkin–Elmer 241 instrument with a Na lamp
(589 nm, continuous). Circular dichroism spectra were
recorded with a JASCO J-715 spectropolarimeter. LRMS
data were acquired using a Varian CH-4 or SM1 spec-
trometer with the ionizing voltage at 70 eV while
HRMS were measured in the ESI or EIMS mode using
an Applied Biosystems/Scix (Q-STA) spectrometer. The
enantiomeric excess was determined by chiral HPLC Agi-
lent 1100.
Figure 2. Projection onto the methacrolein Ca-Si face in the solid state
structure of the complex [Ru((R,R)-BIPHOP-F)Cp(methacrolein)][SbF6]
and the trajectory of the nitrile oxide 8e. This model for the [3+2] cycload-
dition reaction predicts the isoxazoline product to have the 5S configuration.
4.2. Ligand synthesis
4.2.1. Bis(pentafluorophenyl)bromophosphine (C6F5)2PBr
(3).24,25 A solution of bromopentafluorobenzene (1) (49.5 g,
200 mmol) in Et2O (40 mL) was added dropwise to dry
magnesium turnings (8.5 g, 350 mmol) in 80 mL of Et2O.
The dropwise addition was performed at reflux. The mixture
was stirred overnight at rt before being transferred into
a dropping funnel over a flask containing PCl3 (8.73 mL,
100 mmol, 1 equiv) in diethyl ether (60 mL) cooled to
0 ꢀC. The Grignard reagent (C6F5)MgBr (2) was added drop-
wise over 3 h under vigorous stirring. The mixture was al-
lowed to warm to rt for 1 h. The reaction mixture was
filtered through a Celite pad under N2. The solvent was re-
moved under vacuum and the crude product was purified
by fractional distillation under reduced pressure. Bis(penta-
fluorophenyl)bromophosphine (3) (bp: 120 ꢀC, 1.8 mbar)
was obtained as a green-yellow oil (26.4 g, 59%), which
solidified to a pale yellow waxy solid when stored in the
freezer. 31P NMR (162 MHz, CDCl3): d¼12.2 (m, 1P, J¼
35.6 Hz); 19F NMR (376 MHz, CDCl3): d¼33.9 (m, 4F),
15.7 (ddd, J¼20.6, 4.6, 4.6 Hz, 2F), 2.7 (m, 8F).
and nitrile oxide adds to the Ca-Si face of the activated enal
predicting the product to have the configuration S as depicted
in the schemes shown above.
3. Conclusions
The first chiral one-point binding catalyst for the [3+2] cy-
cloaddition of aryl nitrile oxides to methacrolein is reported.
Modest to very good product enantioselectivities are found
and a model rationalizing the regioselectivity and the asym-
metric induction is presented. While the mode of stereo-
chemical control is efficient and well understood, the
reaction suffers from the rather weak activation provided
by the transition metal Lewis acid. The Lewis acid strength
of the catalyst resembles that of ZnCl2. Research in this area
now focuses on the development of catalysts with higher
Lewis acidity but similar geometric features.
4.2.2. (R,R)-Hydrobenzoin-bis(pentafluorophenyl phos-
phite) (R,R)-BIPHOP-F (5).9b (+)-(R,R)-Hydrobenzoin
(4) (2 g, 9.33 mmol), prepared from trans-stilbene by Sharp-
less asymmetric dihydroxylation as described in the litera-
ture26 was dissolved in THF (60 mL). Freshly distilled
NEt3 (3.14 mL, 22.4 mmol) was added and the solution
was cooled to ꢁ78 ꢀC. Then, a solution of bis(pentafluoro-
phenyl)bromophosphine (3) (4.86 mL, 20.53 mmol) in
THF (20 mL) was added dropwise. The reaction mixture
was allowed to warm up slowly to rt and was stirred for
24 h. After filtration over Celite the solvent was removed
in vacuo. The crude product was purified by flash chromato-
graphy (pentane/CH2Cl2 40:1 to pentane/CH2Cl2 4:1). Com-
pound 5 was obtained as a white solid (8.6 g, 92%). IR
4. Experimental
4.1. General
[Ru((R,R)-BIPHOP-F)Cp(methacrolein)][SbF6] (7) was
synthesized from 5 as described in our previously reported
procedures.9c,d,f Hydroximoylchlorides, nitrile oxide precur-
sors, were synthesized from commercially available alde-
hydes following the literature procedures.19 Reactions
were carried out under a positive pressure of nitrogen unless
otherwise stated. Glassware was oven-dried, and further
dried by placing under vacuum and heating with a heat

Y. Brinkmann et al. / Tetrahedron 63 (2007) 8413–8419
8417
(CH2Cl2, cmꢁ1): 3054, 2911, 1640, 1586, 1517, 1480, 1380,
1290, 1270, 1202, 1143, 1091, 980, 918, 882, 88, 800, 762,
638, 584; [a]D25 +85 (c 2.26, CH2Cl2); mp: 118 ꢀC; 1H NMR
(400 MHz, CDCl3): d¼7.05–7.16 (6H, m), 6.98 (4H, dd,
J¼8.3, 1.5 Hz), 5.18 (1H, d, J¼5.6 Hz), 5.15 (1H, d,
J¼5.6 Hz). 13C NMR (100 MHz, C6D6): d¼147, 143, 138,
136, 135, 129, 128, 113, 89. 31P NMR (162 MHz, CDCl3):
d¼88.5 (sept, J¼31.2 Hz, 2P); 19F NMR (376 MHz,
C6D6): d¼31.6 (m, 4F), 31.0 (m, 4F), 15.5 (m, 2F), 14.4
(m, 2F), 2.7 (m, 8F); MS (70 eV) m/z: 561 (100), 381 (65),
365 (55), 180 (78); Elemental analysis, calcd for
C38H12F20O2P2: C, 48.43; H, 1.28. Found: C, 48.54; H, 1.50.
4.4.1. 5-Methyl-3-(2,4,6-trimethyl-phenyl)-4,5-dihydro-
isoxazole-5-carbaldehyde (10a). The catalytic reaction
was stopped at the appropriate reaction time. Hexane was
added to precipitate 7 and after filtering over Celite, the
crude was purified by column chromatography to afford
1
pure 10a. IR (CHCl3, cmꢁ1): 1735, 1613, 1517, 1434; H
NMR (200 MHz, CD2Cl2): d¼9.81 (s, 1H), 6.96 (s, 2H),
3.55 (d, J¼15.0 Hz, 1H), 3.00 (d, J¼15.0 Hz, 1H), 2.36 (s,
3H), 2.28 (s, 6H), 1.68 (s, 3H); 13C NMR (100 MHz,
CD2Cl2): d¼199.4, 158.4, 139.3, 136.6, 128.7, 125.6, 88.6,
45.1, 21.3, 19.9, 19.8.
4.4.2. [5-Methyl-3-(2,4,6-trimethyl-phenyl)-4,5-dihydro-
isoxazol-5-yl]-methanol (12a). Compound 12a was ob-
tained following the general procedures or by reduction of
10a under standard conditions followed by flash chro-
matography. IR (CHCl3, cmꢁ1): 3384, 2921, 1435, 1334,
1260; HPLC: Chiracel OJ-H, hex/i-prop 95:5, 1 mL/min,
60 min, 72% ee; [a]2D5 +70 (c 0.1, CHCl3); 1H NMR
(300 MHz, CDCl3): d¼6.93 (m, 2H), 3.80 (d, J¼12.0 Hz,
1H), 3.62 (d, J¼12.0 Hz, 1H), 3.40 (d, J¼16.0 Hz, 1H),
2.86 (d, J¼16.0 Hz, 1H), 2.31 (s, 3H), 2.30 (s, 3H), 2.28
(br s, 1H), 1.49 (s, 3H); 13C NMR (75 MHz, CDCl3):
d¼158.1, 138.7, 136.5, 128.4, 126.4, 86.5, 67.2, 46.1,
23.0, 21.7, 19.6; MS (EI): m/z: 233 (24), 202 (68), 160
(100); HRMS (ESI+) calcd for C14H20NO2 [M+1]+:
234.1494; found: 234.1499.
4.3. General procedures for 1,3-dipolar cycloaddition
reactions of aromatic nitrile oxides and methacrolein
4.3.1. Generation of nitrile oxides. Nitrile oxides were gen-
erated directly prior to use by stirring hydroximoylchloride
(60 mg) with the resin Amberlyst 21 (120 mg) in dry
CH2Cl2 (1.5 mL) at rt. After completion of the reaction
(30 min to 2 h) the solution of nitrile oxide was syringed up
and the resin was rinsed with additional 0.5 mL of CH2Cl2.
Stable and storable mesityl nitrile oxide (methyl substituents
in o,o0 positions18) did not need an in situ generation.
4.3.2. Synthesis of racemic isoxazolines. For HPLC analy-
sis racemic isoxazolines have been synthesized by reaction
of freshly generated nitrile oxide (1 equiv) with methacro-
lein (10 equiv) in CH2Cl2 at rt. After completion of the reac-
tion the solvent was evaporated and the crude aldehyde was
diluted in THF/H2O (4:1). The solution was cooled to 0 ꢀC
and NaBH4 (excess) was added slowly, then the reaction
was allowed to reach rt. After 2 h the mixture was again
cooled to 0 ꢀC before being hydrolyzed with H2O. Phases
were separated and the aqueous layer was extracted two
times with AcOEt. The organic layers were dried over anhy-
drous Na2SO4, filtered, and the solvent was evaporated under
reduced pressure. The crude product was purified by flash
chromatography affording the pure alcohol.
4.4.3. 5-[5-Methyl-3-(2,4,6-trimethyl-phenyl)-4,5-dihy-
dro-isoxazol-5-yl]-3-(2,4,6-trimethyl-phenyl)-[1,4,2]-di-
oxazole (diastereoisomers 56:44) (11a). The diastereomeric
mixture of acetal 11a has been isolated by column chromato-
graphy of the crude reduction product. IR (CHCl3, cmꢁ1):
2921, 1611, 1435, 1332, 1077; 1H NMR (400 MHz,
CDCl3) (major diastereoisomer (56%)): d¼6.91 (s, 2H),
6.89 (s, 2H), 6.13 (1H), 3.43 (d, J¼17.5 Hz, 1H), 2.97 (d,
J¼17.45 Hz, 1H), 2.40 (s, 6H), 2.37 (s, 6H), 2.22 (s, 6H),
1.65 (s, 3H); 1H NMR (400 MHz, CDCl3) (minor diastereo-
isomer (44%)): d¼6.92 (s, 2H), 6.88 (s, 2H), 6.08 (1H), 3.42
(d, J¼17.7 Hz, 1H), 2.96 (d, J¼17.7 Hz, 1H), 2.30 (s, 6H),
2.28 (s, 6H), 2.22 (s, 6H), 1.64 (s, 3H); 13C NMR
(75 MHz, CDCl3): d¼158.3, 156.9, 140.9, 138.9, 136.6,
128.6, 125.7, 118.7, 109.0, 85.4, 45.9, 21.7, 21.2, 20.1,
19.5; MS (TS) m/z: 233 (24), 202 (68), 160 (100); HRMS
(ESI+) m/z calcd for C24H29N2O3 [M+H]+: 393.2172; found:
393.2173.
4.4. General procedures for catalyzed reactions of nitrile
oxides (8a–g) with methacrolein (9)
Compounds 12a–g have been obtained following the general
procedure unless otherwise stated. [Ru (acetone) (R,R)-(BI-
PHOP-F)(Cp)][SbF6] (7) (26 mg, 5 mol %, 0.02 mmol) was
dissolved in CH2Cl2 (0.5 mL), then methacrolein (47 mL,
0.56 mmol, 1.5 equiv) was added dropwise under stirring.
The solution was cooled to the reaction temperature
(ꢁ5 ꢀC or ꢁ20 ꢀC) and a solution of freshly generated nitrile
oxide (50 mg, 0.38 mmol, 1 equiv) in CH2Cl2 (2 mL) was
added slowly with a syringe pump over 10 h. After stirring
for the appropriate reaction time the solvent was evaporated
and the residue was taken up in THF/H2O (4:1, 10 mL). The
solution was cooled to 0 ꢀC, NaBH4 (excess) was added
slowly, and then the reaction was allowed to reach rt. After
2 h the mixture was again cooled to 0 ꢀC before being hydro-
lyzed with H2O, phases were separated and the aqueous
layer was extracted twice with AcOEt. The organic layers
were dried over anhydrous Na2SO4, filtered, and the solvent
was evaporated under reduced pressure. The crude was puri-
fied by flash chromatography affording the pure alcohol.
Enantiomeric excess was determined by chiral HPLC.
4.4.4. [5-Methyl-3-(4-methyl-phenyl)-4,5-dihydro-isox-
azol-5-yl]-methanol (12b). IR (CHCl3, cmꢁ1): 3394, 2964,
2933, 1600, 1492, 1261; HPLC: Chiracel OD-H, hex/i-prop
grad 99:1 to 90:10, 1 mL/min, 60 min, 66% ee; [a]2D5 +48
(c 1, CHCl3); 1H NMR (200 MHz, CDCl3): d¼7.53 (d,
J¼8.0 Hz, 2H), 7.16 (d, J¼8.0 Hz, 2H), 3.72 (d, J¼
12.0 Hz, 1H), 3.56 (d, J¼12.0 Hz, 1H), 3.45 (d, J¼
16.4 Hz, 1H), 3.00 (d, J¼16.4 Hz, 1H), 2.35 (s, 3H), 1.86
(br s, 1H), 1.40 (s, 3H); 13C NMR (50 MHz, CDCl3): d¼
157.0, 140.2, 129.3, 126.9, 126.5, 87.2, 67.2, 22.6, 21.4;
MS (EI): m/z: 205 (16), 174 (45), 132 (100); HRMS (EI+)
calcd for C12H15NO2 [M]+: 205.1103; found: 205.1103.
4.4.5. [5-Methyl-3-(4-isopropyl-phenyl)-4,5-dihydro-isox-
azol-5-yl]-methanol (12c). IR (CDCl3, cmꢁ1): 3369,
2961, 2930, 1611, 1460, 1418, 1361, 1058, 910, 834;

8418
Y. Brinkmann et al. / Tetrahedron 63 (2007) 8413–8419
HPLC: Chiracel OJ-H, hex/i-prop grad 99:1 to 90:10, 1 mL/
1.43 (s, 3H); 13C NMR (75 MHz, CDCl3): d¼162.0, 156.0,
128.5, 125.9, 115.7, 87.6, 67.2, 42.0, 22.6; MS (TS): m/z
210 (100), 192 (83), 164 (63); HRMS (ESI+) calcd for
C11H13NO2F [M+H]+: 210.0924; found: 210.0935.
1
min, 60 min, 63% ee; [a]2D5 +38 (c 1, CHCl3), H NMR
(400 MHz, CDCl3): d¼8.14 (d, J¼8.0 Hz, 2H), 7.81 (d,
J¼8.0 Hz, 2H), 4.29 (dd, J¼4.3, 3 Hz, 1H), 4.13 (dd,
J¼12.0, 8.5 Hz, 1H), 4.04 (d, J¼16 Hz, 1H), 3.56 (d, J¼
16 Hz, 1H), 3.49 (m, 1H), 2.32 (br s, 1H), 1.98 (s, 3H),
1.82 (s, 3H), 1.80 (s, 3H); 13C NMR (75 MHz, CDCl3):
d¼157.0, 151.2, 127.2, 126.7, 126.6, 87.2, 67.2, 42.1,
34.0, 23.8, 22.6; MS (EI): m/z: 233 (23), 202 (60), 160
(100), 43 (49). HRMS (ESI+) m/z calcd for C14H20NO2
[M+H]+: 234.1488; found: 234.1482.
4.4.9. [5-Methyl-3-(4-chloro-phenyl)-4,5-dihydro-isox-
azol-5-yl]-methanol (12g). IR (CHCl3, cmꢁ1): 3391, 2929,
1597, 1495; 1403, 1354; HPLC: Chiracel OJ-H, hex/i-prop
grad 95:5 to 85:15, 1 mL/min, 120 min, 77% ee; [a]2D5 +47
(c 0.98, CHCl3), 1H NMR (300 MHz, CDCl3): d¼7.52
(d, J¼8.0 Hz, 2H), 7.31 (d, J¼8.0 Hz, 2H), 3.71 (d, J¼
12.0 Hz, 1H), 3.53 (d, J¼12.0 Hz, 1H), 3.44 (d, J¼
16.7 Hz, 1H), 2.93 (d, J¼16.7 Hz, 1H), 2.82 (br s, 1H),
1.39 (s, 3H); 13C NMR (75 MHz, CDCl3): d¼155.9, 135.8,
128.8, 128.1, 127.7, 87.8, 67.0, 41.6, 22.5; MS (TS): m/z
226 (56), 154 (52), 152 (100); HRMS (ESI+) calcd for
C11H13NO2Cl [M+H]+: 226.0636; found: 226.0629.
4.4.6. [5-Methyl-3-(4-methoxy-phenyl)-4,5-dihydro-isox-
azol-5-yl]-methanol (12d). [Ru (acetone) (R,R)-(BIPHOP-
F)(Cp)][SbF6] (70.12 mg, 5 mol %, 0.05 mmol) was
dissolved in CH2Cl2 (1.5 mL), then methacrolein (124 mL,
0.56 mmol, 1.5 equiv) was added dropwise under stirring.
The solution was cooled to ꢁ5 ꢀC and a solution of freshly
generated nitrile oxide (149.15 mg, 1 mmol, 1 equiv) in
CH2Cl2 (6.5 mL) was added slowly with a syringe pump
for 10 h. After 17 h hexane was added (20 mL), to precipi-
tate the catalyst, CH2Cl2 was removed under vacuum, the
solution was filtered through a Celite plug, the catalyst
was eluted with acetone, and recycled following our previ-
ously published procedures.9c,d,f The reduction and purifica-
tion of the crude reaction was carried out as stated in the
general procedures. Pure [3-(4-methoxy-phenyl)-5-methyl-
4,5-dihydro-isoxazol-5-yl]-methanol was obtained as
a pale yellow solid (157 mg, 71% yield, 63% ee). IR (CHCl3,
cmꢁ1): 3503, 2924, 2853, 1607, 1594, 1457, 1437, 1249;
HPLC: Chiracel OD-H, hex/i-prop grad 95:5 to 85:15,
1 mL/min, 120 min, 65% ee; [a]2D5 +45 (c 0.59, CHCl3),
1H NMR (500 MHz, CDCl3): d¼7.63 (d, J¼8.4 Hz, 2H),
6.95 (d, J¼8.4 Hz, 2H), 3.88 (s, 3H), 3.75 (d, J¼12.0 Hz,
1H), 3.60 (d, J¼12.0 Hz, 1H), 3.48 (d, J¼16.4 Hz, 1H),
3.04 (d, J¼16.4 Hz, 1H), 1.89 (br s, 1H), 1.46 (s, 3H); 13C
NMR (125 MHz, CDCl3): d¼160.9, 156.6, 128.06, 122.2,
114.0, 87.0, 67.2, 55.3, 42.2, 22.6; MS (EI): m/z: 221 (29),
190 (45), 148 (100). HRMS (EI+) calcd for C12H15NO3
[M]+: 221.1052; found: 221.1051.
4.4.10. (5-Methyl-3-phenyl-4,5-dihydro-isoxazol-5-yl)-
methanol (12h). The reaction was carried out following
the standard procedure starting from 100 mg of phenyl
nitrile oxide (0.84 mmol), ꢁ5 ꢀC, 22 h, 60% yield. IR
(CHCl3, cmꢁ1): 3378, 2929, 1597, 1446, 1359; HPLC: Chir-
acel OJ-H, hex/i-prop grad 95:5 to 85:15, 1 mL/min,
1
120 min, 60% ee; [a]D25 +27 (c 0.98, MeOH), H NMR
(300 MHz, CDCl3): d¼7.64 (m, 2H), 7.38 (m, 3H), 3.72
(d, J¼12.0 Hz, 1H), 3.57 (d, J¼12.0 Hz, 1H), 3.49 (d,
J¼16.7 Hz, 1H), 2.99 (d, J¼16.7 Hz, 1H), 2.45 (br s, 1H),
1.41 (s, 3H); 13C NMR (75 MHz, CDCl3): d¼157.0, 130.0,
129.7, 128.6, 126.5, 87.45, 67.1, 41.9, 22.6; MS (TS): m/z:
192 (100), 174 (18). HRMS (ESI+): calcd for C11H14NO2
[M+H]+: 192.1019; found: 192.1019.
4.4.11. 5-Methyl-3-phenyl-4,5-dihydro-isoxazole-5-carb-
oxylic acid (13). The compound was synthesized following
the literature procedures.21 The crude acid was then purified
by flash chromatography (30:1 EtOAc/AcOH) to afford 13
as a white solid. IR (CHCl3, cmꢁ1): 2934, 1722, 1447,
1446; 1360; [a]2D5 +35 (c 0.48, CHCl3), 1H NMR (300 MHz,
CDCl3): d¼7.64 (m, 2H), 7.41 (m, 3H), 3.88 (d, J¼
16.3 Hz, 1H), 3.28 (d, J¼16.3 Hz, 1H), 1.77 (s, 3H); 13C
NMR (75 MHz, CDCl3): d¼176.1, 156.9, 130.6, 128.8,
128.5, 126.8, 85.8, 44.9, 23.2; MS (TS): m/z: 206 (100),
188 (76), 160 (20). HRMS (ESI+) calcd for C11H12NO3
[M+H]+: 206.0811; found: 206.0819.
4.4.7. [5-Methyl-3-(4-trifluoromethyl-phenyl)-4,5-di-
hydro-isoxazol-5-yl]-methanol (12e). IR (CHCl3, cmꢁ1):
3384, 2921, 1435, 1327; HPLC: Chiracel OD-H, hex/i-
prop grad 99:1 to 90:10, 1 mL/min, 60 min, 93% ee; [a]D25
+57 (c 0.49, CHCl3), 1H NMR (200 MHz, CDCl3): d¼7.81
(d, J¼8.0 Hz, 2H), 7.74 (d, J¼8.0 Hz, 2H), 3.89 (dd,
J¼12.0, 4.0 Hz, 1H), 3.65 (dd, J¼12.0, 4.0 Hz, 1H), 3.67
(d, J¼16.0 Hz, 1H), 3.13 (d, J¼16.0 Hz, 1H), 1.19 (br s,
1H), 1.52 (s, 3H); 13C NMR (75 MHz, CDCl3): d¼154.9,
142.1, 138.5, 132.7 (q, J¼0.8 Hz, CF3), 126.7, 125.6,
125.5, 88.3, 67.2, 41.6, 22.0; MS (EI): m/z: 259 (8), 228
(53), 186 (100). HRMS (ESI+) calcd for C12H12NO2F3Na
[M+Na]+: 282.0717; found: 282.0719.
Acknowledgements
We are grateful for financial support from the University of
Geneva and the Swiss National Science Foundation.
References and notes
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1
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Data were corrected for Lorentz and polarization effects and
for absorption. (C11H12NO2Cl), Mr¼225.7, monoclinic,
˚
P21/c, a¼11.6995(13), b¼10.5564(8), c¼9.1556(12) A, b¼
3
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