Cobalt-catalyzed aerobic oxidative cyclization of β,γ- unsaturated oximes

Article abstract of DOI:10.1016/j.tet.2013.02.032

Cobalt complex Co(nmp)₂ can efficiently catalyze the aerobic oxidative 5-exo cyclization of β,γ-unsaturated oximes to afford isoxazolines. The key cyclization step involves the generation of carbon-centred radicals. The products are largely dep

Full text of DOI:10.1016/j.tet.2013.02.032

Tetrahedron 69 (2013) 3274e3280
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Cobalt-catalyzed aerobic oxidative cyclization of
oximes
b,g-unsaturated
*
Weifei Li, Pingjing Jia, Bing Han, Dianjun Li, Wei Yu
State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou 730000, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Cobalt complex Co(nmp)2 can efficiently catalyze the aerobic oxidative 5-exo cyclization of
b,g-un-
Received 16 December 2012
Received in revised form 28 January 2013
Accepted 4 February 2013
saturated oximes to afford isoxazolines. The key cyclization step involves the generation of carbon-
centred radicals. The products are largely dependent on the reaction conditions. The oxidative termi-
nation products 2 were produced predominantly when the reaction was carried out in i-PrOH, whereas
the reductive termination products 3 were selectively obtained in toluene in the presence of cyclohexa-
1,4-diene.
Available online 13 February 2013
Keywords:
Aerobic oxidation
Cyclization
Ó 2013 Elsevier Ltd. All rights reserved.
Cobalt catalysis
Unsaturated oximes
Isoxazolines
1. Introduction
which employs bis (5,5-dimethyl-1-(4- methylpiperazin-1-yl)hex-
ane-1,2,4-trione) cobalt (II) (Co(nmp)2) and 10 mol % of TBHP as
Transition metal-catalyzed aerobic oxygenation of olefins is not
only an important process in chemical industry, but also of great
value in current organic synthesis.1 The studies by Mukaiyama et al.
catalyst.6 The later procedure is advantageous in terms of simplified
purification as well as high product yield.6
Isoxazolines are important intermediates in organic synthesis.
Besides the commonly used 1,3-dipolar addition reactions between
nitrile oxides and alkenes, isoxazolines can be accessed through the
CeO forming cyclization of unsaturated oximes.7,8 In this context,
have demonstrated that bis(b-diketonato) cobalt complexes can
efficiently catalyze the aerobic oxygenation of olefins in the pres-
ence of a reductant, which is usually a secondary alcohol used as
solvent.2 The process was named as ‘oxidationereduction hydra-
tion’. When this methodology was applied to 5-hydroxy-1-alkenes,
a highly stereoselective synthesis of 2-hydroxymethyl tetrahydro-
furans was developed.3,4 The reaction is largely dependent on the
structural properties of cobalt catalysts, and yields can be improved
by the addition of tert-butyl hydroperoxide (tBuOOH, TBHP). Har-
tung et al. later conducted a series of detailed investigations on this
reaction with an aim to extend its synthetic scope and enhance the
efficacy.5 Their studies reveal that using bis{2,2,2-trifluoromethyl-
an aerobic oxidative cyclization of b,g-unsaturated oximes has been
recently achieved by using Pd(OAc)2 as catalyst.9 This protocol is
attractive in that it employs the economical and environmentally
benign oxygen as oxidant to realize the dioxygenation of alkenes.
Considering the catalytic capacity of cobalt complexes in the oxy-
genation of olefins, we envisioned that cobalt catalysts would also
be applicable to this type of oxidative cyclization. We examined the
effects of several cobalt(II) salts and complexes, and found that
Co(nmp)2 was highly effective to prompt the reaction. Moreover,
both oxidative termination products and reductive termination
products can be selectively obtained, depending on the reaction
conditions (Scheme 1).
1-[(1R,4S)-1,7,7-trimethyl-2-(oxo-
ethanolato-
O}cobalt(II) (CoL12) or bis{4-[3,5-bis(trifluoromethyl)
phenyl]-2-(oxo- O)-but-3-en-4eolato- O}cobalt(II) as catalyst can
kO)bicyclo[2.2.1] hept-3-yliden]
k
k
k
obviate the use of TBHP. In addition, when the reaction is per-
formed in toluene in the presence of cyclohexa-1,4-diene (CHD),
the reductive termination products will be obtained in high yield. In
another study, Pagenkopf et al. developed an improved procedure,
OH
R3
OH
R4
10 mol% Co(nmp)2
20 equiv. CHD
toluene, 60 °C, air
10 mol% Co(nmp)2
0.1 equiv. TBHP
O
N
O
N
N
R4
R4
R1
R3
R1
R1
R3
i-PrOH, 55 °C, O2
R2
R2
R2
* Corresponding author. E-mail addresses: yuwei@lzu.edu.cn, wyjs1990@
163.com (W. Yu).
Scheme 1. Cobalt-catalyzed cyclization of unsaturated oximes.
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.02.032

W. Li et al. / Tetrahedron 69 (2013) 3274e3280
3275
CF3
OH
2. Results and discussion
O
OH
NMe
N
We initiated this study by subjecting compound 1a to several
cobalt complexes and salts under oxygen atmosphere. The results
are summarized in Table 1. Bis{2,2,2-trifluoromethyl-1-[(1R,4S)-
O
O
L1
nmp
Fig. 1. Structures of ligand L1 and nmp.
1,7,7-trimethyl-2-(oxo-
kO)bicyclo[2.2.1] hept-3-yliden] ethanolato-
k
O}cobalt(II) (CoL12) and bis (5,5-dimethyl-1-(4- methylpiperazin-
1-yl)hexane-1,2,4-trione) cobalt (II) (Co(nmp)2) (Fig. 1), which can
effectively prompt the oxidative cyclization of 5-hydroxy-1-alkenes
as reported, respectively by Hartung et al.5 and Pagenkopf et al.,6
are capable of effecting the cyclization of 1a in i-PrOH. Com-
pound 2a was obtained in good yield when the reaction was per-
formed under Pagenkopf’s conditions (Table 1, entry 6). Running
the reaction in several other solvents led to inferior results.
Co(OAc)2, Co(acac)2 and CoBr2 also exhibited catalytic capacity, but
they were not as effective as Co(nmp)2. In some cases, a small
amount of 3a was isolated along with compound 2a. Control ex-
periments showed that the reaction also took place in the absence
of cobalt catalyst when it was run in AcOH or toluene, but the yield
of 2a was low (Table 1, entries 17, 18).
Table 2
Co(nmp)2-catalyzed aerobic cyclization of unsaturated oximesa
Entry
Substrate
Product(s)
Yield (%)b
78
OH
O
N
N
1
OH 2a
Ph
Ph
1a(E)
OH
O
N
N
2
3
4
76
92
55
OH 2b
p-MeO-Ph
p-MeO-Ph
HO
1b (E)
1c (Z)
O
N
N
OH 2c
As can be seen in Table 1, Co(nmp)2 performed the best among
the catalysts screened when used together with 0.1 equiv of TBHP
(Table 1, entry 6). These conditions were then applied to a variety of
p-CN-Ph
p-CN-Ph
OH
O
N
N
differently substituted b,g-unsaturated oximes (2be2m) and a,b-
OH 2d
t-Bu
t-Bu
1d (E)
unsaturated oxime 2n. The results are shown in Table 2. The re-
action proceeded smoothly for all the chosen substrates, resulting
in the formation of 4,5-dihydroisoxazoles in good yields. The sub-
stituents did not influence the reaction consequence much, albeit
that the yield was a little lower for 2d and 2g. When compounds 1i,
1l and 1m were used, the corresponding isoxazolines were ob-
tained as a mixture of two diastereoisomers. In the case of com-
pound 2n, 5-endo cyclization took place under the reaction
conditions (Table 2, entry 14). It is noteworthy that both E and Z
isomers of 1 can be converted to products 2, and the initial con-
figuration of the substrates has no apparent influence on the re-
action rate.
OH
N
O
O
N
N
5
6
81
65
OH 2e
Ph(CH2)2
1e
Ph(CH2)2
(E/Z)
OH
N
OH 2f
n-Pentyl
n-Pentyl
1f (Z)
OH
N
O
N
7
8
60
81
OH 2g
2-Thienyl
1g
2-Thienyl
(E/Z)
OH
N
O
N
OH
2-Furyl
1h
2-Furyl
Ph
2h
(E/Z)
Table 1
Screening of the conditions for the oxidative cyclization of 1a
OH
O
N
N
83 (dr¼35:65)c
OH
9
Ph
Me
2i
Me
OH
1i (E/Z)
O
N
N
Products/yield (%)a
OH
OH
Entry
CoL2 (mol %)
Additive (equiv)
Solvent
10
77
62
Ph
Ph
Me
Co(L1)2 (10)
Co(L1)2 (10)
Co(L1)2 (10)
Co(L1)2 (10)
Co(nmp)2 (10)
Co(nmp)2 (10)
Co(nmp)2 (5)
Co(nmp)2 (10)
Co(nmp)2 (10)
Co(nmp)2 (10)
Co(OAc)2 (10)
Co(acac)2 (10)
Co(acac)2 (10)
CoCl2 (10)
None
i-PrOH
i-PrOH
i-PrOH
AcOH
i-PrOH
i-PrOH
i-PrOH
EtOH
2a/54, 3a/db
2a/42, 3a/db
2a/47, 3a/db,c
2a/21, 3a/db,c
2a/60, 3a/6
Me Me
OH
2j
Me
1
2
3
4
1j (E)
1k (E)
TBHP (1.0)
TBHP (0.1)
TBHP (0.1)
None
TBHP (0.1)
TBHP (0.1)
TBHP (0.1)
TBHP (0.1)
TBHP (0.1)
TBHP (0.1)
TBHP (0.1)
None
O
N
N
Me
11
12
Me
Ph
2k
Ph
Ph
5
6f
7
2a/78, 3a/tracec
2a/21, 3a/11
2a/30, 3a/db
2a/43, 3a/6
OH
O
N
N
65
(cis:trans
¼42:58)
OH
N
8
9
Ph
c
MeCN
AcOH
Ph
2l
Ph
OH
2a/31, 3a/db
2a/40, 3a/6
2a/37, 3a/7
1l (E)
10
11
12
13
14
15
16
17
18
i-PrOH
i-PrOH
i-PrOH
i-PrOH
i-PrOH
i-PrOH
AcOH
O
O
OH
OH
N
N
13
81
Ph
Ph
(2m-1:2m-2
2a/29, 3a/7
Ph
¼35:65)c
TBHP (0.1)
TBHP (0.1)
TBHP (0.1)
None
2a/10, 3a/db
2a/39, 3a/10
n.d.c,d
2m-1
2m-2
1m (E/Z)
CoBr2 (10)
None
None
None
OH
Me
2a/31, 3a/db,e
2a/37, 3a/5 þS.M.
O
N
N
PPh3 (1.0)
Toluene
14
73
Ph
Ph
OH 2n
a
Me
Isolated yields. The reaction time was 16 h unless otherwise specified.
Not isolated.
The reaction time was 5 h.
With 1a being recovered.
Treated with PPh3 after reaction.
The optimal reaction conditions.
1n (E/Z)
b
c
d
e
f
a
The reaction was carried out on 1.0 mmol scale. Conditions: 10 mol % Co(nmp)2,
10 mol % TBHP (70% in water), 5 mL i-PrOH, O2 (in balloon), 55 ꢀC.
b
Isolated yields.
Determined by GCeMS and 1H NMR.
c

3276
W. Li et al. / Tetrahedron 69 (2013) 3274e3280
In the above-mentioned reactions, besides compounds 2, a tiny
ring opening under both conditions A and B, indicating that the
cyclization step involves the generation of carbon-centred radicals
(Scheme 5). However, apart from the SET mechanism, the radical II
could also derive from the 5-exo-trig cyclization of oxime radicals
(Scheme 4(b)). Our recent work shows that oxime radicals can be
conveniently generated from the reaction of oximes with DEAD
(diethyl azodicarboxylate).10 As a matter of fact, Co(II) salts, such as
Co(OAc)2 and Co(acac)2, have been well known to be capable of
facilitating the generation of phthalimido-N-oxyl (PINO) radical
from N-hydroxyphthalimide (NHPI) under aerobic conditions.11
Considering the structural analogy of oxime radicals to PINO, it is
possible that Co(III)OOꢁ radicals can convert oximes to oxime rad-
icals as well. In fact, the bond dissociation energy (BDE) of the OeH
bond in oximes is even lower (about 83 kcal/mol on average)12 than
in NHPI (about 88 kcal/mol).11 Therefore, we assume that the
transformations of 1 to 4,5-dihydroisoxazoles 2 and 3 follow, at
least partly, the mechanism shown in path (b) of Scheme 4. This
hypothesis is supported by the observations that the reaction of 1a
occurred moderately with Co(OAc)2 as catalyst, or in AcOH and
toluene in the absence of cobalt (Table 1). By contrast, Co(OAc)2 is
ineffective for the cyclization of 5-hydroxy-1-alkenes.
amount of reductive termination products 3 were also generated in
some cases. Further experiments showed that compounds 3 could
became dominant when the reaction was performed in toluene in
the presence of 20 equiv of CHD.5bed As such, with the air as ter-
minal oxidant, compounds 3 were generated mostly in good yields
from 1 (Scheme 2). For the reactions of compounds 1i and 1l,
a diasteroselectivity of roughly 3:1 was observed, respectively,
which was higher than their counterparts shown in Table 2. On the
other hand, when compound 1n was used as the substrate, the
expected 3n did not form. Instead, the reaction afforded 2n in yield
of 71%.
Scheme 4. Possible reaction mechanism.
Scheme 2. The reaction of 1 in toluene under air in the presence of CHD.
Although these protocols are effective for the cyclization of
b,g-
unsaturated oximes, they are not applicable to -unsaturated
g,d
oximes for similar transformations. When compound 4 was sub-
jected to the reaction conditions shown in Table 2, no reaction took
place, with only the starting materials being recovered. On the
other hand, under the conditions of reductive termination, the re-
action led to a complex mixture (Scheme 3).
Scheme 5. Evidence to support a free radical process.
InthecasewhereconditionsAwere applied, compound9 was also
obtained along with the ring-opening product 8. Probably the higher
oxygen concentration here rendered the trapping of radical I by O2 to
be competitive with the ring opening process. This trend was re-
flected too when the reaction was carried out in the presence of ac-
tivated alkenes. As shown in Scheme 6, when 1a was subjected to
Scheme 3. The results with gamma,delta-unsaturated oxime 4 under the present
conditions.
The mechanistic aspects of the cobalt-catalyzed aerobic oxy-
genation of olefins have been of much interest. It is believed that in
general, the first step is the oxidation of Co(II) by oxygen, from
which Co(III)L2OOꢁ radical is produced.2 Concerning the cobalt-
mediated cyclization of 5-hydroxy-1-alkenes, Hartung proposes
that the key step involves the single electron transfer (SET) from the
double bond to the hydroxyl-binded Co(III)L2OOꢁ radical.5a The
tetrahydrofuran ring forms subsequently, affording the tetrahy-
drofuran-2-yl methyl radicals, which are then trapped by oxygen or
CHD.5b The current cyclization of oximes might be rationalized by
this mechanism as well (Scheme 4(a)). Indeed, when the protocol
was applied to compound 5, the cyclopropyl ring in 5 underwent
Scheme 6. Traping experiment with diethyl maleate.

W. Li et al. / Tetrahedron 69 (2013) 3274e3280
3277
Co(nmp)2 in toluene in the presence of 5 equiv of CHD and 10 equiv of
diethyl maleate at 60 ꢀC in the air, compound 10 was obtained in 18%
yield, together with compound 3a. On the other hand, the reaction
only led to the formation of compound 2a under conditions A.
resulting solution was stirred at 60 ꢀC in the air. After the reaction
finished as indicated by TLC, The reaction mixture was cooled to
20 ꢀC and concentrated under reduced pressure. The residual was
purified by chromatography to give product 3.5b Compounds 6, 7
and 8 were obtained in the same way.
3. Conclusion
4.4. Characterization data for the products
In summary, we have demonstrated that the aerobic oxidative
cyclization of
b
,
g
-unsaturated oximes can be achieved by using
4.4.1. (3-Phenyl–4,5-dihydroisoxazol-5-yl)methanol
(2a). White
cobalt complex Co(nmp)2 as catalyst. When the reactions are car-
ried out in i-PrOH with 1 atm of O2 as the oxidant, the major
products are the oxidative termination products 2. On the other
hand, conducting the reaction in toluene in the air in the presence
of 20 equiv of CHD would predominantly result in the formation of
reductive termination products 3. This work provides an alternative
protocol for the synthesis of 4,5-dihydroisoxazoles.
solid, mp 83e84 ꢀC, Rf¼0.30 (petroleum ether:ethyl acetate¼1:1);
1H NMR (CDCl3, 400 MHz,
d ppm): d 7.68e7.66 (m, 2H), 7.41 (d,
J¼4.8 Hz, 3H), 4.91e4.84 (m, 1H), 3.89e3.86 (m, 1H), 3.72e3.66 (m,
1H), 3.39 (dd, J¼16.8, 10.8 Hz, 1H), 3.29 (dd, J¼16.4, 8.0 Hz, 1H), 2.30
(br, 1H); 13C NMR (CDCl3, 100 MHz,
d ppm): d 157.1, 130.2, 129.3,
128.7, 126.7, 81.2, 63.6, 36.3; EI-MS m/z (rel int., %): 177 (Mþ, 49.8),
146 (87.5), 118 (100.0), 91(30.9), 77 (80.4).
4. Experimental
4.4.2. (3-(4-Methoxyphenyl)-4,5-dihydroisoxazol-5-yl)methanol
(2b). Pale yellow solid, mp 140e141 ꢀC, Rf¼0.26 (petroleum
4.1. General information
ether:ethyl acetate¼1:1); 1H NMR (CDCl3, 400 MHz,
d ppm): d 7.59
(d, J¼8.8 Hz, 2H), 6.90 (d, J¼8.8 Hz, 2H), 4.86e4.80 (m, 1H),
3.87e3.83 (m, 1H), 3.83 (s, 3H), 3.67 (dd, J¼12.4, 4.8 Hz, 1H), 3.35
(dd, J¼16.4, 10.4 Hz, 1H), 3.25 (dd, J¼16.4, 8.0 Hz, 1H), 2.42 (br, 1H);
Chemicals and solvents were purified by standard methods.
Reaction progress was monitored with thin layer chromatography
(TLC) performed on GF254 silica gel plates. Flash chromatography
13C NMR (CDCl3, 100 MHz,
d ppm): d 161.1, 156.6, 128.2, 121.8, 114.1,
was carried out with silica gel (200e300 mesh).
80.9, 63.6, 55.3, 36.5; EI-MS m/z (rel int., %): 207 (Mþ, 100.0), 176
13
The 1H and
C NMR spectra were recorded on a Bruker AM-
(82.4), 148 (53.9), 121 (92.6), 107 (11.2), 92(15.5).
400 MHz spectrometer. All the spectra were obtained in deuterated
chloroform and were referred to residual chloroform at 7.27 ppm
for 1H spectra and the center peak of the triplet at 77.0 (t) for 13
d
4.4.3. 4-(5-(Hydroxymethyl)-4,5-dihydroisoxazol-3-yl)benzonitrile
d
C
(2c). White solid, mp 144e145 ꢀC, Rf¼0.35 (petroleum ether:ethyl
spectra. The EI-MS spectra were measured on an HP 5988A spec-
trometer by direct inlet at 70 eV. The high resolution mass spectra
(HRMS) were measured on a Bruker Daltonics APEX II 47e spec-
trometer by ESI. Melting points were measured on an XT-4 melting
point apparatus and were uncorrected.
acetate¼1:1); 1H NMR (CDCl3, 400 MHz,
d
ppm):
d
7.78 (d, J¼8.4 Hz,
2H), 7.70 (d, J¼8.4 Hz, 2H), 4.98e4.92 (m, 1H), 3.97e3.91 (m, 1H),
3.74e3.68 (m, 1H), 3.39 (dd, J¼16.4, 10.8 Hz, 1H), 3.32 (dd, J¼16.4,
8.0 Hz, 1H), 1.93e1.89 (m, 1H); 13C NMR (CDCl3, 100 MHz,
d ppm):
d
155.8, 133.6, 132.4, 127.1, 118.2, 113.4, 82.2, 63.4, 35.5; EI-MS m/z
2-(2-Phenyltetrahydrofuran-2-yl)acetaldehyde,13 bis{2,2,2-trifluo-
(rel int., %): 202 (Mþ, 28.7), 185 (2.0), 171 (69.3), 155 (16.7), 143
(100.0), 129 (52.4).
romethyl-1-[(1R,4S)-1,7,7-trimethyl-2-(oxo-kO) bicyclo[2.2.1]hept-
3-yliden]ethanolato-k
O} cobalt(II) (CoL02),5a and bis(5,5-dimethyl-1-
(4- methylpiperazin-1-yl)hexane-1,2,4-trione) cobalt(II) (Co(nmp)2)6
were prepared according to the reported procedures. Compounds
1ae1n were prepared as previously reported.9
4.4.4. (3-(tert-Butyl)-4,5-dihydroisoxazol-5-yl)methanol
(2d). Colourless oil, Rf¼0.44 (petroleum ether:ethyl acetate¼1:1);
1H NMR (400 MHz, CDCl3,
d ppm): d 4.67e4.61 (m, 1H), 3.74e3.70
(m, 1H), 3.57e3.52 (m, 1H), 3.00 (dd, J¼16.8, 10.4 Hz, 1H), 2.86 (dd,
4.2. General procedure for the syntheses of 2ae2m
J¼16.8, 7.2 Hz, 1H), 2.36 (br, 1H), 1.19 (s, 9H); 13C NMR (CDCl3,
100 MHz,
d ppm): d 166.5, 80.1, 63.7, 35.7, 33.0, 28.0; EI-MS m/z (rel
b,
g-Unsaturated oxime 1 (1.0 mmol) was added into 5 mL of i-
int., %): 157 (Mþ, 16.6), 142 (1.5), 126 (49.2), 84 (10.4), 57 (100.0).
PrOH contained in a flask charged with Co(nmp)2 (0.1 mmol) under
1 atm of O2 (balloon) at room temperature. Then 0.1 mmol of tert-
butyl hydroperoxide (TBHP) (70% in water) was added in one por-
tion into the mixture under stirring, and the resulting solution was
heated to 55 ꢀC and stirred at that temperature for 5 h. The reaction
mixture was cooled to room temperature, purged of O2 with argon,
4.4.5. (3-Phenethyl-4,5-dihydroisoxazol-5-yl)methanol (2e). Pale yel-
low oil, Rf¼0.52 (petroleum ether:ethyl acetate¼1:1); 1H NMR
(CDCl3, 400 MHz,
d ppm): d 7.31e7.26 (m, 2H), 7.22e7.19 (m, 3H),
4.66e4.60 (m, 1H), 3.71 (dd, J¼12.0, 3.2 Hz, 1H), 3.52 (dd, J¼12.0,
4.8 Hz, 1H), 2.95e2.88 (m, 3H), 2.79 (dd, J¼17.2, 7.6 Hz, 1H),
and treated with methyl iodide (62
mL, 1.0 mmol, 1.0 equiv). After
2.68e2.64 (m, 2H), 2.41 (br, 1H); 13C NMR (CDCl3, 100 MHz,
d ppm):
stirring for another 5 h, the mixture was concentrated under re-
duced pressure and the residual was dissolved in 20 mL of CH2Cl2,
followed by addition of 20 mL of water. The layers were separated,
and the aqueous layer was extracted with CH2Cl2 (4ꢂ20 mL). The
combined organic layers were washed with brine, dried over
MgSO4, filtered through Celite and concentrated under reduced
pressure.6 The residual was treated with flash chromatography to
afford 2. Compounds 2n and 9 was obtained in the same way.
d 158.8, 140.4, 128.5, 128.2, 126.3, 80.0, 63.5, 38.6, 32.5, 29.3; EI-MS
m/z (rel int., %): 205 (Mþ, 47.1), 174 (66.9), 146 (72.5), 118 (20.2),
105 (57.3), 91 (100.0).
4.4.6. (3-Pentyl-4,5-dihydroisoxazol-5-yl)methanol (2f). Colourless
oil, Rf¼0.40 (petroleum ether:ethyl acetate¼1:1); 1H NMR (CDCl3,
400 MHz, d ppm): d 4.67e4.61 (m, 1H), 3.82e3.61 (m, 1H), 3.55 (dd,
J¼12.0, 4.0 Hz, 1H), 3.00e2.92 (m, 1H), 2.82 (dd, J¼17.2, 7.6 Hz, 1H),
2.32 (t, J¼7.6 Hz, 2H), 1.57e1.53 (m, 2H), 1.33e1.29 (m, 4H), 0.88 (t,
4.3. General procedure for the syntheses of 3ae3m
J¼6.6 Hz, 3H); 13C NMR (CDCl3, 100 MHz,
d ppm): d 159.6, 79.8, 63.7,
38.4, 31.3, 27.5, 25.9, 22.2, 13.8; EI-MS m/z (rel int., %): 171 (Mþ, 1.7),
b,
g-Unsaturated oxime 1 (1.0 mmol) and cyclohexa-1,4-diene
149 (5.1), 115 (20.1), 71 (25.7), 43 (100.0).
(CHD) (20 mmol) were consecutively added into 5 mL of toluene
contained in a 10 mL round bottom flask charged with Co(nmp)2
(0.10 mmol). The flask was then equipped with a condenser, and the
4.4.7. (3-(Thiophen-2-yl)-4,5-dihydroisoxazol-5-yl)methanol
(2g). Yellow solid, mp 95e96 ꢀC, Rf¼0.36 (petroleum ether:ethyl

3278
W. Li et al. / Tetrahedron 69 (2013) 3274e3280
acetate¼1:1); 1H NMR (CDCl3, 400 MHz,
d
ppm):
d
7.39e7.37 (m,
ether:ethyl acetate¼1:1); 1H NMR (CDCl3, 400 MHz,
d ppm):
1H), 7.21e7.20 (m, 1H), 7.06e7.05 (m, 1H), 4.88e4.83 (m, 1H), 3.86
(d, J¼12.0 Hz, 1H), 3.68 (dd, J¼12.0, 4.4 Hz, 1H), 3.49e3.27 (m, 2H),
d
7.66e7.63 (m, 2H), 7.42e7.41 (m, 3H), 4.44 (dd, J¼8.4, 4.8 Hz 1H),
4.13e4.10 (m, 1H), 3.68 (dd, J¼15.2, 8.0 Hz, 1H), 2.57 (br, 1H),
1.96e1.92 (m, 1H), 1.85e1.80 (m, 1H), 1.68e1.62 (m, 2H), 1.55e1.41
2.44 (br, 1H); 13C NMR (CDCl3, 100 MHz,
d ppm): d 152.8, 131.7,
128.6, 128.3, 127.3, 81.5, 63.4, 37.1; EI-MS m/z (rel int., %): 183 (Mþ,
(m, 2H), 1.40e1.37 (m, 1H); 13C NMR (CDCl3, 100 MHz,
d ppm):
99.3), 152 (82.0), 124 (70.3), 105 (27.2), 97 (100.0).
d 162.9, 130.1, 128.8, 128.8, 127.0, 84.8, 66.9, 44.5, 28.4, 24.7, 17.7; EI-
MS m/z (rel int., %): 217 (Mþ,100.0),188 (12.3),158 (28.6),132 (47.7),
4.4.8. (3-(Furan-2-yl)-4,5-dihydroisoxazol-5-yl)methanol (2h) (new
compound). Pale yellow oil, Rf¼0.34 (petroleum ether:ethyl
104 (63.0).
acetate¼1:1); 1H NMR (CDCl3, 400 MHz,
d
ppm):
d
7.50 (s, 1H), 6.70
4.4.15. (7R*,
7aR*)-3-phenyl-3a,4,5,6,7,7a-hexahydrobenzo[d]iso-
(d, J¼3.6 Hz, 1H), 6.47 (t, J¼1.6 Hz, 1H), 4.85e4.79 (m, 1H), 3.84 (dd,
J¼12.4, 3.2 Hz, 1H), 3.66 (dd, J¼12.0, 4.8 Hz, 1H), 3.34 (dd, J¼16.8,
10.8 Hz, 1H), 3.24 (dd, J¼16.8, 8.0 Hz, 1H), 2.48 (br, 1H); 13C NMR
xazol-7-ol (2m-2). Pale yellow solid, mp 114e115 ꢀC, Rf¼0.36 (pe-
troleum ether:ethyl acetate¼1:1); 1H NMR (CDCl3, 400 MHz,
d
ppm):
d
7.71e7.69 (m, 2H), 7.42e7.41 (m, 3H), 4.63 (dd, J¼7.6,
(CDCl3, 100 MHz,
d
ppm):
d
149.2, 144.6, 144.4, 112.0, 111.6, 81.0,
4.0 Hz, 1H), 4.04e4.01 (m, 1H), 3.54e3.50 (m, 1H), 2.32 (br, 1H),
1.96e1.90 (m, 2H), 1.82e1.75 (m, 1H), 1.71e1.61 (m, 1H), 1.44e1.34
63.3, 36.1; EI-MS m/z (rel int., %): 167 (Mþ, 100.0), 136 (95.2), 108
(73.7), 81 (51.5), 53 (25.8); ESI-HRMS: m/z Calcd for C8H9NO3þHþ:
168.0655, found 168.0650.
(m, 2H); 13C NMR (CDCl3, 100 MHz,
d ppm): d 163.4, 130.2, 128.8,
128.7, 126.9, 82.3, 68.9, 46.1, 28.7, 25.4, 21.3; EI-MS m/z (rel int., %):
217 (Mþ, 67.3), 188 (11.3), 158 (33.4), 132 (51.2), 104 (100.0).
4.4.9. (3-Phenyl-4-methyl-4,5-dihydroisoxazol-5-yl)methanol
(2i,
dr¼35:65). Colourless oil, Rf¼0.27 (petroleum ether:ethyl
4.4.16. 4-Methyl-3-phenyl-4,5-dihydroisoxazol-4-ol
(2n). White
acetate¼1:1); 1H NMR (CDCl3, 400 MHz,
d
ppm):
d
7.69e7.66 (m,
solid, mp 83e84 ꢀC, Rf¼0.74 (petroleum ether:ethyl acetate¼1:1);
3.20H), 7.42e7.41 (m, 4.17H), 4.75e4.69 (m, 0.24H) 4.46e4.43 (m,
1H), 3.97e3.95 (m, 0.59H), 3.79e3.70 (m, 1.32H), 3.67e3.60 (m,
2.14H), 2.14 (br, 1.18H), 1.35 (d, J¼7.2 Hz, 3.37H), 1.27e1.22 (m, 1H);
1H NMR (CDCl3, 400 MHz,
d ppm): d 7.80e7.78 (m, 2H), 7.42e7.34
(m, 3H), 4.38 (d, J¼9.6 Hz, 1H), 4.21 (d, J¼10.0 Hz, 1H), 3.30 (br, 1H),
1.62 (s, 3H); 13C NMR (CDCl3, 100 MHz,
d ppm): d 160.6, 130.0, 128.6,
13C NMR (CDCl3, 100 MHz,
d
ppm):
d
162.2, 130.1, 128.8, 128.6, 127.1,
127.5, 127.4, 85.2, 82.0, 23.2; EI-MS m/z (rel int., %): 177 (Mþ, 39.0),
127.1, 84.0, 60.7, 43.1, 11.5; EI-MS m/z (rel int., %): 191 (Mþ, 40.3),160
149 (4.6), 135 (5.4), 104 (97.5), 43 (100.0).
(81.8), 132 (86.2), 117 (100.0), 104 (35.8), 77(71.5).
4.4.17. 5-Methyl-3-phenyl-4,5-dihydroisoxazol (3a). White solid,
mp 51e52 ꢀC, Rf¼0.44 (petroleum ether:ethyl acetate¼10:1); 1H
4.4.10. (4,4-Dimethyl-3-phenyl-4,5-dihydroisoxazol-5-yl)methanol
(2j). Colourless oil, Rf¼0.50 (petroleum ether:ethyl acetate¼1:1); 1H
NMR (CDCl3, 400 MHz, d ppm): d 7.69e7.66 (m, 2H), 7.41e7.39 (m,
NMR (CDCl3, 400 MHz,
d
ppm):
d
7.63e7.60 (m, 2H), 7.43e7.39 (m,
3H), 4.93e4.84 (m, 1H), 3.43 (dd, J¼16.4, 10.0 Hz, 1H), 2.93 (dd,
3H), 4.32 (dd, J¼6.8, 4.0 Hz, 1H), 3.91e3.78 (m, 2H), 2.38 (br, 1H), 1.46
J¼16.4, 8.0 Hz,1H),1.44 (d, J¼6.0 Hz, 3H); 13C NMR (CDCl3,100 MHz,
(s, 3H), 1.31 (s, 3H); 13C NMR (CDCl3, 100 MHz,
d
ppm): 164.9, 129.7,
d
d ppm): d 156.4, 129.9, 129.8, 128.6, 126.5, 77.4, 41.5, 20.9; EI-MS m/z
128.9, 128.6, 127.5, 90.5, 60.9, 50.7, 25.9, 18.9; EI-MS m/z (rel int., %):
(rel int., %): 161(Mþ, 100.0), 147 (4.8), 131 (9.1), 118 (33.1), 91 (17.3).
205 (Mþ, 50.0),175 (12.6),174 (100.0),147 (14.7),131 (87.1),104 (56.0).
4.4.18. 3-(4-Methoxyphenyl)-5-methyl-4,5-dihydroisoxazole
4.4.11. (5-Methyl-3-phenyl-4,5-dihydroisoxazol-5-yl)methanol
(3b). White solid, mp 104e105 ꢀC, Rf¼0.19 (petroleum ether:ethyl
(2k). Colourless oil, Rf¼0.51 (petroleum ether:ethyl acetate¼1:1);
acetate¼10:1); 1H NMR (CDCl3, 400 MHz,
d ppm): d 7.63e7.59 (m,
1H NMR (CDCl3, 400 MHz,
d
ppm):
d
7.68e7.65 (m, 2H), 7.42e7.40
2H), 6.94e6.90 (m, 2H), 4.90e4.81 (m, 1H), 3.85 (s, 3H), 3.41 (dd,
J¼16.4, 10.0 Hz, 1H), 2.91 (dd, J¼16.0, 8.0 Hz, 1H), 1.43 (d, J¼6.4 Hz,
(m, 3H), 3.75 (d, J¼12.0 Hz, 1H), 3.62e3.57 (m, 1H), 3.50 (d,
J¼16.8 Hz, 1H), 3.03 (d, J¼16.4 Hz, 1H), 2.06 (br, 1H), 1.45 (s, 3H); 13C
3H); 13C NMR (CDCl3, 100 MHz,
d ppm): d 160.9, 156.0, 128.1, 122.5,
NMR (CDCl3, 100 MHz,
d
ppm):
d
157.1, 130.0, 129.8, 128.7, 126.6,
114.1, 77.3, 55.3, 41.8, 20.9; EI-MS m/z (rel int., %): 191 (Mþ, 100.0),
87.4, 67.3, 42.0, 22.7; EI-MS m/z (rel int., %): 191 (Mþ, 14.9), 160
176 (15.4), 161 (8.4), 148 (21.9), 121 (40.0).
(42.0), 118 (100.0), 77 (16.4), 43 (13.7).
4.4.19. 4-(5-Methyl-4,5-dihydroisoxazol-3-yl)benzonitrile (3c) (new
compound). White solid, mp 91e92 ꢀC, Rf¼0.17 (petroleum
4.4.12. ((4S*,5S*)-3,4-Diphenyl-4,5-dihydroisoxazol-5-yl)methanol
(2l-1). White solid, mp 99e100 ꢀC, Rf¼0.63 (petroleum ether:ethyl
ether:ethyl acetate¼10:1); 1H NMR (CDCl3, 400 MHz,
d ppm): d 7.74
acetate¼1:1); 1H NMR (CDCl3, 400 MHz,
d
ppm):
d
7.59e7.57 (m,
(d, J¼8.4 Hz, 2H), 7.67e7.64 (m, 2H), 4.98e4.88 (m, 1H), 3.42 (dd,
J¼16.4, 10.4 Hz, 1H), 2.92 (dd, J¼16.4, 8.4 Hz, 1H), 1.43 (d, J¼6.4 Hz,
2H), 7.34e7.24 (m, 8H), 4.71(d, J¼6.0 Hz, 1H), 4.65e4.61 (m, 1H),
3.90 (d, J¼11.6 Hz, 1H), 3.77 (d, J¼12.0 Hz, 1H), 2.08 (br, 1H); 13C
3H); 13C NMR (CDCl3, 100 MHz,
d ppm): d 155.1, 134.1, 132.3, 126.9,
NMR (CDCl3, 100 MHz,
d
ppm):
d
158.7, 139.0, 129.9, 129.3, 128.8,
118.2, 113.0, 78.4, 40.7, 20.8; EI-MS m/z (rel int., %): 186 (Mþ, 100.0),
171 (25.3), 143 (98.1), 129 (25.9), 102 (54.6); ESI-HRMS: m/z Calcd
for C11H10N2OþHþ: 187.0866, found 187.0860.
128.5, 127.7, 127.6, 127.3, 90.5, 63.2, 55.7; EI-MS m/z (rel int., %): 253
(Mþ, 41.5), 222 (34.6), 193 (100.0), 165 (25.0), 91 (65.8).
4.4.13. ((4S*,5R*)-3,4-Diphenyl-4,5-dihydroisoxazol-5-yl)methanol
(2l-2) (new compound). White solid, mp 88e89 ꢀC, Rf¼0.52 (pe-
troleum ether:ethyl acetate¼1:1); 1H NMR (CDCl3, 400 MHz,
4.4.20. 3-(tert-Butyl)-5-methyl-4,5-dihydroisoxazole (3d) (new com-
pound). Colourless oil, Rf¼0.47 (petroleum ether:ethyl acetate¼10:1);
1H NMR (CDCl3, 400 MHz,
d ppm): d 4.71e4.62 (m, 1H), 3.03 (dd,
d
ppm):
d
7.57 (d, J¼6.8 Hz, 2H), 7.32e7.26 (m, 6H), 7.17 (d, J¼7.2 Hz,
J¼16.4, 9.6 Hz, 1H), 2.53 (dd, J¼16.4, 8.0 Hz, 1H), 1.31 (d, J¼6.0 Hz, 3H),
2H), 4.96e4.90 (m, 1H), 4.78 (d, J¼10.0 Hz, 1H), 3.56e3.44 (m, 2H),
1.20 (s, 9H); 13C NMR (CDCl3, 100 MHz,
d ppm): d 165.9, 76.4, 40.9,
1.57 (br, 1H); 13C NMR (CDCl3, 100 MHz,
d
ppm): 159.6, 133.4,
d
32.9, 28.0, 20.7; EI-MS m/z (rel int., %): 141 (Mþ, 38.4), 126 (100.0), 97
(42.4), 82 (64.9), 57 (22.4); ESI-HRMS: m/z Calcd for C8H15NOþHþ:
142.1226, found 142.1224.
130.0, 129.1, 128.7, 128.6, 128.1, 127.3, 85.2, 61.6, 55.4; EI-MS m/z (rel
int., %): 253 (Mþ, 41.4), 222 (99.0), 193 (13.9), 165 (18.5), 91 (100.0);
ESI-HRMS: m/z Calcd for C16H15NO2þHþ: 254.1176, found 254.1181.
4.4.21. 5-Methyl-3-phenethyl-4,5-dihydroisoxazole (3e). White solid,
mp 35e36 ꢀC, Rf¼0.27 (petroleum ether:ethyl acetate¼10:1); 1H
4.4.14. (7S*,
7aR*)-3-phenyl-3a,4,5,6,7,7a-hexahydrobenzo[d]iso-
xazol-7-ol (2m-1). White solid, mp 86e87 ꢀC, Rf¼0.37 (petroleum
NMR (CDCl3, 400 MHz, d ppm): d 7.33e7.29 (m, 2H), 7.24e7.21 (m,

W. Li et al. / Tetrahedron 69 (2013) 3274e3280
3279
3H), 4.71e4.62 (m, 1H), 2.99e2.90 (m, 3H), 2.69e2.65 (m, 2H), 2.47
(dd, J¼16.8, 7.6 Hz, 1H), 1.30 (d, J¼6.0 Hz, 3H); 13C NMR (CDCl3,
1.6 Hz, 2H), 7.33e7.21 (m, 8H), 4.67e4.61 (m, 1H), 4.30 (d, J¼5.6 Hz,
1H), 1.47 (d, J¼6.4 Hz, 3H); 13C NMR (CDCl3, 100 MHz,
d ppm):
100 MHz,
d
ppm):
d
158.2, 140.6, 128.5, 128.2, 126.3, 76.2, 43.9, 32.6,
d 157.9, 139.1, 129.6, 129.2, 128.5, 128.4, 127.6, 127.5, 127.2, 86.8, 61.2,
29.6, 20.7; EI-MS m/z (rel int., %): 189 (Mþ, 29.8),174 (8.6),145 (12.8),
20.6; EI-MS m/z (rel int., %): 237 (Mþ, 15.2), 193 (100.0), 165 (24.1),
129 (2.3), 91 (100.0).
117 (26.8), 91 (13.4).
4.4.22. 3-Pentyl-5-methyl-4,5-dihydroisoxazole (3f). Pale yellow oil,
Rf¼0.44 (petroleum ether:ethyl acetate¼10:1). 1H NMR (CDCl3,
4.4.29. (4S*,5S*)-5-Methyl-3,4-diphenyl-4,5-dihydroisoxazole (3l-2)
(new compound). White solid, mp 97e98 ꢀC, Rf¼0.48 (petroleum
400 MHz,
d
ppm):
d
4.70e4.60 (m, 1H), 2.98 (dd, J¼16.4, 10.0 Hz,
ether:ethyl acetate¼10:1); 1H NMR (CDCl3, 400 MHz,
d ppm):
1H), 2.48 (dd, J¼16.4, 8.0 Hz, 1H), 2.32 (t, J¼7.6 Hz, 2H), 1.58e1.51
d
7.63e7.61 (m, 2H), 7.36e7.16 (m, 6H), 7.15 (d, J¼7.2 Hz, 2H),
(m, 2H), 1.33e1.29 (m, 7H), 0.88 (t, J¼6.8 Hz, 3H); 13C NMR (CDCl3,
4.98e4.91 (m, 1H), 4.54 (d, J¼9.2 Hz, 1H), 1.08 (d, J¼6.8 Hz, 3H); 13C
100 MHz,
d
ppm):
d
159.0, 76.0, 43.6, 31.3, 27.7, 26.0, 22.2, 20.8, 13.8;
NMR (CDCl3, 100 MHz, d ppm): d 160.4, 134.3, 129.8, 129.4, 128.9,
EI-MS m/z (rel int., %): 155 (Mþ, 100.0), 140 (45.9), 129 (29.6), 112
128.7, 128.6, 127.8, 127.1, 81.9, 57.1, 14.4; EI-MS m/z (rel int., %): 237
(Mþ,15.2),193 (100.0),165 (24.1), 91 (13.4), 77 (13.1); ESI-HRMS: m/
z Calcd for C16H15NOþHþ: 238.1226, found 238.1230.
(37.8), 99 (73.7).
4.4.23. 5-Methyl-3-(thiophen-2-yl)-4,5-dihydroisoxazole (3g) (new
compound). Light red oil, Rf¼0.29 (petroleum ether:ethyl
4.4.30. 3-Phenyl-3a,4,5,6,7,7a-hexahydrobenzo[d]isoxazole
acetate¼10:1). 1H NMR (CDCl3, 400 MHz,
d
ppm):
d
7.38 (dd, J¼5.2,
(3m). White solid, mp 86e87 ꢀC, Rf¼0.43 (petroleum ether:ethyl
0.8 Hz, 1H), 7.19 (dd, J¼3.6, 0.8 Hz, 1H), 7.06 (dd, J¼5.2, 3.6 Hz, 1H),
4.93e4.84 (m, 1H), 3.45 (dd, J¼16.4, 10.0 Hz, 1H), 2.95 (dd, J¼16.4,
8.0 Hz, 1H), 1.44 (d, J¼6.0 Hz, 3H); 13C NMR (CDCl3, 100 MHz,
acetate¼10:1); 1H NMR (CDCl3, 400 MHz,
d ppm): d 7.74e7.70 (m,
2H), 7.43e7.38 (m, 3H), 4.52e4.48 (m, 1H), 3.30e3.24 (m, 1H), 2.27
(dd, J¼15.2, 2.8 Hz, 1H), 2.01e1.96 (m, 1H), 1.82e1.50 (m, 4H),
d
ppm):
d
152.2, 132.5, 128.0, 128.0, 127.2, 77.8, 42.4, 20.8; EI-MS m/z
1.32e1.22 (m, 2H); 13C NMR (CDCl3,100 MHz,
d ppm): d 163.9,129.9,
(rel int., %): 167 (Mþ, 100.0), 152 (19.1), 124 (25.6), 111 (18.2), 97
(43.8); ESI-HRMS: m/z Calcd for C8H9NOSþHþ: 168.0478, found
168.0475.
129.4, 128.7, 126.8, 80.3, 44.4, 26.4, 25.0, 22.3, 20.2; EI-MS m/z (rel
int., %): 201 (Mþ, 100.0), 184 (9.1), 172 (19.8), 158 (25.9), 144 (28.0).
4.4.31. 5-(But-1-en-1-yl)-3-phenyl-4,5-dihydroisoxazole (6) (new com-
pound). White solid, Rf¼0.57 (petroleum ether:ethyl acetate¼10:1).
4.4.24. 3-(Furan-2-yl)-5-methyl-4,5-dihydroisoxazole (3h) (new com-
pound). Pale yellow oil, Rf¼0.33 (petroleum ether:ethyl
1H NMR (CDCl3, 400 MHz,
d ppm): d 7.69e7.66 (m, 2H), 7.40 (t,
acetate¼10:1); 1H NMR (CDCl3, 400 MHz,
d
ppm):
d
7.50 (d, J¼1.2 Hz,
J¼3.2 Hz, 3H), 5.89 (dt, J¼15.2, 6.4 Hz 0.88H), 5.63e5.61 (m, 0.13H),
5.59 (ddt, J¼8.0, 7.6, 2.0 Hz, 1H), 5.53e5.45 (m, 0.12H), 5.13 (dd,
J¼18.4, 8.8 Hz, 0.88H), 3.49e3.42 (m, 1H), 3.13e3.06 (m, 1H),
2.15e2.07 (m, 2H), 1.03 (t, J¼7.6 Hz, 3H); 13C NMR (CDCl3, 100 MHz,
1H), 6.68 (d, J¼3.6 Hz, 1H), 6.48 (dd, J¼3.6,1.6 Hz,1H), 4.88e4.79 (m,
1H), 3.38 (dd, J¼16.4, 10.0 Hz, 1H), 2.89 (dd, J¼16.4, 8.0 Hz, 1H), 1.41
(d, J¼6.4 Hz, 3H); 13C NMR (CDCl3, 100 MHz,
d ppm): d 148.7, 145.2,
144.1, 111.6, 111.4, 77.3, 41.4, 20.7; EI-MS m/z (rel int., %): 151 (Mþ,
100.0), 129 (7.1), 108 (23.1), 91 (17.0), 81 (28.4); ESI-HRMS: m/z Calcd
for C8H9NO2þHþ: 152.0706, found 152.0702.
d ppm): d 156.5, 137.2, 129.9, 129.7, 128.6, 126.9, 126.6, 82.4, 41.1, 40.5,
25.1, 21.1, 14.2, 13.0; EI-MS m/z (rel int., %): 201 (Mþ, 69.8), 172 (58.0),
145 (22.7), 117 (73.4), 91 (29.2); ESI-HRMS: m/z Calcd for
C13H15NOþHþ: 202.1226, found 202.1221.
4.4.25. 4,5-Dimethyl-3-phenyl-4,5-dihydroisoxazole (3i, 4.5 cis:trans
¼27:73). Colourless
oil,
Rf¼0.51
(petroleum
ppm):
ether:ethyl
7.72e7.66 (m,
4.4.32. 4-(3-Phenyl-4,5-dihydroisoxazol-5-yl)but-3-en-1-ol (7) (new
compound). White solid, Rf¼0.37 (petroleum ether:ethyl
acetate¼10:1); 1H NMR (CDCl3, 400 MHz,
d
d
2.61H), 7.43e7.37 (m, 3.91H), 4.71e4.65 (m, 0.26H), 4.48e4.42 (m,
1H), 3.50e3.45 (m, 0.25H), 3.33e3.26 (m, 1H), 1.44 (d, J¼6.4 Hz,
0.78H),1.35 (d, J¼6.0 Hz, 3H),1.29 (d, J¼7.2 Hz, 3H),1.12 (d, J¼7.6 Hz,
acetate¼1:1); 1H NMR (CDCl3, 400 MHz,
d ppm): d 7.68e7.66 (m,
2H), 7.42e7.40 (m, 3H), 5.90e5.83 (m, 1H), 5.76e5.71 (m, 1H), 5.16
(dd, J¼18.0, 8.4 Hz, 1H), 3.72 (t, J¼6.4 Hz, 2H), 3.48 (dd, J¼16.4,
6.4 Hz, 1H), 3.12 (dd, J¼16.4, 8.8 Hz, 1H), 2.37 (dd, J¼13.2, 6.4 Hz,
0.83H); 13C NMR (CDCl3, 100 MHz,
d ppm): d 162.7, 160.4, 129.8,
129.6, 129.2, 129.1, 128.7, 128.6, 126.8, 126.8, 84.7, 80.5, 48.5, 43.8,
20.1, 17.3, 13.1, 11.5; EI-MS m/z (rel int., %): 175 (Mþ, 88.8), 160 (8.0),
130 (100.0), 117 (34.7),77 (37.8).
2H), 1.62 (br, 1H); 13C NMR (CDCl3, 100 MHz,
d ppm): d 156.5, 131.3,
130.8, 130.1, 129.6, 128.7, 126.7, 81.9, 61.7, 40.6, 35.5; EI-MS m/z (rel
int., %): 217 (Mþ, 39.4), 187 (10.5), 172 (50.6), 146 (39.7), 117 (100.0);
ESI-HRMS: m/z Calcd for C13H15NO2þNaþ: 240.0995, found
240.0999.
4.4.26. 4,4,5-Trimethyl-3-phenyl-4,5-dihydroisoxazole (3j) (new com-
pound). White solid, mp 53e54 ꢀC, Rf¼0.56 (petroleum ether:ethyl
acetate¼10:1). 1H NMR (CDCl3, 400 MHz,
d
ppm):
d
7.68e7.64 (m,
4.4.33. 4-Hydroxy-1-(3-phenyl-4,5-dihydroisoxazol-5-yl)butan-2-
one (8) (new compound). White solid, mp 71e72 ꢀC, Rf¼0.17 (pe-
troleum ether:ethyl acetate¼1:1); 1H NMR (CDCl3, 400 MHz,
2H), 7.42e7.36 (m, 3H), 4.24 (q, J¼6.4 Hz,1H), 1.34e1.33 (m, 6H),1.21
(s, 3H); 13C NMR (CDCl3,100 MHz,
d ppm): d 165.0, 129.7, 129.4, 128.4,
127.1, 86.7, 50.7, 23.7,19.2,12.4; EI-MS m/z (rel int., %): 189 (Mþ, 74.3),
174 (5.3), 144 (100.0), 131 (18.3), 105 (15.2); ESI-HRMS: m/z Calcd for
C12H15NOþHþ: 190.1226, found 190.1232.
d ppm): d 7.67e7.65 (m, 2H), 7.42e7.40 (m, 3H), 5.16e5.08 (m, 1H),
3.91e3.86 (m, 2H), 3.58 (dd, J¼16.8, 10.4 Hz, 1H), 3.11e3.00 (m, 2H),
2.82e2.74 (m, 3H), 2.37 (br, 1H); 13C NMR (CDCl3, 100 MHz,
d
ppm):
d
208.5, 156.8, 130.2, 129.3, 128.7, 126.7, 80.3, 57.7, 48.2, 45.5, 40.4;
4.4.27. 5,5-Dimethyl-3-phenyl-4,5-dihydroisoxazole (3k). White solid,
mp 58e59 ꢀC, Rf¼0.55 (petroleum ether:ethyl acetate¼10:1); 1H
EI-MS m/z (rel int., %): 233 (Mþ, 1.2), 215 (0.4), 189 (1.0), 161 (1.2),
146 (100.0); ESI-HRMS: m/z Calcd for C13H15NO3þHþ: 234.1125,
found 234.1120.
NMR (CDCl3, 400 MHz,
d ppm): d 7.68e7.64 (m, 2H), 7.41e7.38 (m,
3H), 3.11 (s, 2H), 1.50 (s, 6H); 13C NMR (CDCl3, 100 MHz,
d
ppm):
d
156.2, 130.3, 129.7, 128.6, 126.4, 84.9, 46.7, 27.3; EI-MS m/z (rel int.,
4.4.34. Cyclopropyl (3-phenyl-4,5-dihydroisoxazol-5-yl) methanol
%): 175 (Mþ, 56.5), 160 (36.3), 143 (5.7), 118 (100.0), 91 (13.1).
(9) (new compound). Colourless oil, Rf¼0.67 (petroleum ether:ethyl
acetate¼1:1): 1H NMR (CDCl3, 400 MHz,
d ppm): d 7.71e7.67 (m,
4.4.28. (4S*,5R*)-5-Methyl-3,4-diphenyl-4,5-dihydroisoxazole
(3l-
2H), 7.42e7.41 (m, 3H), 4.88e4.79 (m, 1H), 3.54 (dd, J¼16.8, 8.8 Hz,
0.72H), 3.38e3.28 (m,1.87H), 2.97 (dd, J¼8.4, 4.8 Hz, 0.34H), 2.02 (s,
1H), 1.29e1.24 (m, 2H), 1.08e1.06 (m, 0.55H), 0.90e0.88 (m, 1H),
1). White solid, mp 99e100 ꢀC, Rf¼0.60 (petroleum ether:ethyl
acetate¼10:1); 1H NMR (CDCl3, 400 MHz,
d
ppm):
d
7.58 (dd, J¼7.6,

3280
W. Li et al. / Tetrahedron 69 (2013) 3274e3280
0.63e0.59 (m, 2H), 0.47e0.39 (m, 1H), 0.39e0.38 (m, 1H); 13C NMR
(CDCl3, 100 MHz, ppm): 157.3, 157.1, 130.2, 130.1, 129.5, 128.7,
this article can be found at http://dx.doi.org/10.1016/
j.tet.2013.02.032.
d
d
128.7, 126.7, 84.3, 83.9, 77.3, 77.2, 75.5, 37.0, 34.7, 14.0, 13.0, 2.7, 2.5,
2.4, 2.0; EI-MS m/z (rel int., %): 217 (Mþ, 7.1), 146 (7.2), 134 (19.2),
119 (96.1), 104 (100.0); ESI-HRMS: m/z Calcd for C13H15NO2þNaþ:
240.0995, found 240.0999.
References and notes
1. (a) Punniyamurthy, T.; Velusamy, S.; Iqbal, J. Chem. Rev. 2005, 105, 2329e2363;
(b) Cavani, F.; Teles, J. H. ChemSusChem 2009, 2, 508e534; (c) Gligorich, K. M.;
Sigman, M. S. Chem. Commun. 2009, 3854e3867.
4.4.35. Diethyl 2-((3-phenyl-4,5-dihydroisoxazol-5-yl)methyl) succi-
2. Mukaiyama, T.; Yamada, T. Bull. Chem. Soc. Jpn. 1995, 68, 17e35.
3. Inoki, S.; Mukaiyama, T. Chem. Lett. 1990, 67e70.
nate (10) (new compound). Pale yellow oil, Rf¼0.26 (petroleum
ether:ethyl acetate¼5:1); 1H NMR (400 MHz, CDCl3,
d ppm):
4. For examples of synthetic applications, see: (a) Wang, Z.-M.; Tian, S.-K.; Shi, M.
Tetrahedron Lett. 1999, 40, 977e980; (b) Wang, Z.-M.; Tian, S.-K.; Shi, M. Eur. J.
Org. Chem. 2000, 2, 349e356; (c) Evans, P. A.; Cui, J.; Gharpure, S. J.; Polosukhin,
A.; Zhang, H.-R. J. Am. Chem. Soc. 2003, 125, 14702e14703; (d) Wang, J.; Pa-
genkopf, B. L. Org. Lett. 2007, 9, 3703e3706; (e) Zhao, H.; Gorman, J. S. T.; Pa-
genkopf, B. L. Org. Lett. 2006, 8, 4379e4382.
d
7.68e7.65 (m, 2H), 7.42e7.40 (m, 3H), 4.85e4.78 (m, 1H),
4.23e4.12 (m, 4H), 3.51e3.43 (m, 1H), 3.11e2.96 (m, 2H), 2.84e2.72
(m, 1H), 2.67e2.59 (m, 1H), 2.45e2.17 (m, 0.69H), 2.07e2.04 (m,
0.35H),1.94e1.83 (m,1H),1.30e1.24 (m, 6H), 4.85e4.78 (m, 1H); 13C
ꢀ
NMR (CDCl3, 100 MHz,
d
ppm):
d
174.2, 174.0, 171.6, 171.5, 156.5,
5. (a) Perez, B. M.; Schuch, D.; Hartung, J. Org. Biomol. Chem. 2008, 6, 3532e3541;
ꢀ
(b) Perez, B. M.; Hartung, J. Tetrahedron Lett. 2009, 50, 960e962; (c) Schuch, D.;
130.1, 129.5, 128.7, 126.6, 79.3, 78.8, 61.0, 60.7, 40.6, 40.3, 38.6, 38.4,
37.4, 36.7, 35.7, 14.1; EI-MS m/z (rel int., %): 333 (Mþ, 0.2), 289 (3.8),
261 (0.9), 187 (5.1), 146 (100.0); ESI-HRMS: m/z Calcd for
C18H23NO5þNaþ: 356.1474, found 356.1699.
€
ꢀ
Fries, P.; Donges, M.; Perez, B. M.; Hartung, J. J. Am. Chem. Soc. 2009, 131,
12918e12920; (d) Fries, P.; Halter, D.; Kleinschek, A.; Hartung, J. J. Am. Chem.
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6. Palmer, C.; Morra, N. A.; Stevens, A. C.; Bajtos, B.; Machin, B. P.; Pagenkopf, B. L.
Org. Lett. 2009, 11, 5614e5617.
7. (a) Norman, A. L.; Shurrush, K. A.; Calleroz, A. T.; Mosher, M. D. Tetrahedron Lett.
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49, 4153e4155; (c) Mosher, M. D.; Norman, A. L.; Shurrush, K. A. Tetrahedron
Lett. 2009, 50, 5647e5648.
8. Jiang, D.; Peng, J.; Chen, Y. Org. Lett. 2008, 10, 1695e1698.
9. Zhu, M.-K.; Zhao, J.-F.; Loh, T.-P. J. Am. Chem. Soc. 2010, 132, 6284e6285.
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Acknowledgements
The authors thank the national fund for talent training in basic
science (J1103307) from National Science Foundation of China for
financial support.
11. (a) Ishii, Y.; Sakaguchi, S.; Iwahama, T. Adv. Synth. Catal. 2001, 343, 393e427; (b)
Recupero, F.; Punta, C. Chem. Rev. 2007, 107, 3800e3842.
Supplementary data
12. (a) Pratt, D. A.; Blake, J. A.; Mulder, P.; Walton, J. C.; Korth, H.-G.; Ingold, K. U. J.
Am. Chem. Soc. 2004, 126, 10667e10675; (b) Chong, S.-S.; Fu, Y.; Liu, L.; Guo, Q.-
X. J. Phys. Chem. A 2007, 111, 13112e13125.
13. Ueki, T.; Doe, M.; Tanaka, R.; Morimoto, Y.; Yoshihara, K.; Kinoshita, T. J.
Heterocyclic Chem. 2001, 38, 165e172.
The general experimental methods, all the characterization data
and copies of 1H NMR, 13C NMR spectra for compounds 1, 2, 3, 5e10
are available in Supplementary data. Supplementary data related to