Tandem reaction of propargyl alcohols and N-tosyl hydroxylamine: Switchable synthesis of 2,5-dihydroisoxazoles and 4-halo-2,5-dihydroisoxazoles

Article abstract of DOI:10.1016/j.tet.2012.09.092

2,5-Dihydroisoxazoles, 4-iodo-2,5-dihydroisoxazoles, and 4-bromo-2,5-dihydroisoxazoles were efficiently constructed from propargylic alcohols and N-tosyl hydroxylamine using ytterbium triflate, iodine and N-bromosuccinimide, respectively. N-sulfonylallena

Full text of DOI:10.1016/j.tet.2012.09.092

Tetrahedron 68 (2012) 10194e10200
Contents lists available at SciVerse ScienceDirect
Tetrahedron
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Tandem reaction of propargyl alcohols and N-tosyl hydroxylamine: switchable
synthesis of 2,5-dihydroisoxazoles and 4-halo-2,5-dihydroisoxazoles
*
*
Yuanxun Zhu, Guangwei Yin, Lang Sun, Ping Lu , Yanguang Wang
Department of Chemistry, Zhejiang University, Hangzhou 310027, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 15 July 2012
Received in revised form 13 September 2012
Accepted 21 September 2012
Available online 25 September 2012
2,5-Dihydroisoxazoles, 4-iodo-2,5-dihydroisoxazoles, and 4-bromo-2,5-dihydroisoxazoles were effi-
ciently constructed from propargylic alcohols and N-tosyl hydroxylamine using ytterbium triflate, iodine
and N-bromosuccinimide, respectively. N-sulfonylallenamide is postulated to be the key intermediate for
these tandem transformations. Moreover, the resulting 4-iodo-2,5-dihydroisoxazoles could be elaborated
by palladium-catalyzed carbonylation to generate 4-methoxycarbonyl-4,5-dihydroisoxazoles.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Propargylic alcohols
Hydroxylamines
Allenamides
Dihydroisoxazoles
Tandem reactions
1. Introduction
Isoxazole and dihydroisoxazole moieties are key substructures
in both targets and building blocks for various pharmaceutical
products,1 chemosensor compounds,2 and liquid crystals.3 Much
attention has been paid to the development of efficient methods for
the synthesis of isoxazoles4 and dihydroisoxazoles5e7 due to their
importance.
Although the construction of 2,3-5 and 4,5-dihydroisoxazoles6
has been well established, synthesis of 2,5-dihydroisoxazoles has
been seldom reported. In few examples, 2,5-dihydroisoxazoles
could be elegantly synthesized by
molecular cyclization of O-propargyl hydroxylamines7a,b (Scheme
1, Eq. 1). But to the disappointment, these methods require
p-acid catalyzed intra-
p-
acid, such as gold and the protection groups for NH. As alternative
methods, Knight7c and Wada7d reported efficient accesses to 4-
iodo-2,5-dihydroisoxazoles via iodocyclization of O-propargyl hy-
droxylamines, respectively (Scheme 1, Eq. 2). The starting material,
N-protected O-propynyl hydroxylamine, which was hard to be in-
stalled from propargylic alcohol,7 should be pre-prepared in both
cases. As a result, it is highly desirable to develop a new strategy
that can be carried out under benign conditions without multi-step
synthesis from propargyl alcohols.
Scheme 1. Previous works for the synthesis of 2,5-dihydroisoxazoles and 4-iodo-2,5-
dihydroisoxazoles.
With our continuing research on the development of tandem
reactions of allenamide intermediates,8 we were interested in de-
veloping one-pot tandem approaches to 2,5-dihydroisoxazole
skeleton from the readily available propargylic alcohols and N-
tosyl hydroxylamine. Herein, we would like to report the results of
this effort.
* Corresponding authors. Tel./fax: þ86 571 87951512; e-mail addresses: pinglu@
zju.edu.cn (P. Lu), orgwyg@zju.edu.cn (Y. Wang).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.09.092

Y. Zhu et al. / Tetrahedron 68 (2012) 10194e10200
10195
Table 2
2. Results and discussion
Tandem synthesis of 3a
In our primary experiment, the Lewis acid catalyzed reaction of
propargylic alcohol (1a) and N-tosyl hydroxylamine (2) was ex-
amined (Scheme 2). As we expected, 2,5-dihydroisoxazole (3a) was
isolated in 54% yield when 1a was treated with 2 in the presence of
BF3$Et2O in dichloromethane (DCM) at room temperature for
a short time. To our delight, 4-iodo-2,5-dihydroisoxazole (4a) was
obtained by supplementary addition of NIS. Structures of 3a and 4a
were unambiguously confirmed by X-ray analysis.9
Entry
1 (R1/R2/R3)
Time (h)
Product/yieldb (%)
1
2
3
4
5
6
7
8
1a (Ph/Ph/Ph)
3
2
3
3
3
6
2
3
3
6
6
5
4
3
3
2
3a/82
3b/57
3c/70
3d/81
3e/86c
3f/95c
3g/ndd
3h/43
3i/55
3j/86
3k/85
3l/82
3m/30
3n/46
3o/ndd
3p/46
1b (4-MeOC6H4/4-MeOC6H4/Ph)
1c (4-MeC6H4/4-MeC6H4/Ph)
1d (4-MeC6H4/Ph/Ph)
1e (4-ClC6H4/Ph/Ph)
1f (4-ClC6H4/4-ClC6H4/Ph)
1g (Ph/Me/Ph)
1h (Ph/Ph/4-MeOC6H4)
1i (Ph/Ph/4-MeC6H4)
1j (Ph/Ph/4-FC6H4)
1k (Ph/Ph/4-BrC6H4)
1l (Ph/Ph/3-BrC6H4)
1m (Ph/Ph/2-BrC6H4)
1n (Ph/Ph/n-Bu)
9
10
11
12
13
14
15
16
Scheme 2. Lewis acid catalyzed reactions between 1a and 2.
Due to the advantages of both reactions (without special p-acid
1o (Ph/Ph/H)
1p (Ph/Ph/TMS)
catalysts, mild reaction conditions, and the commercially available
starting materials), we optimized reaction conditions. Optimization
of reaction conditions for the formation of 3a was summarized in
Table 1. By screening the various Lewis acids (Table 1, entries 1e4)
and Brønsted acids (Table 1, entries 5 and 6), ytterbium triflate was
observed to be the optimal catalyst. DCM was selected as the most
suitable solvent among dichloroethane (DCE), acetonitrile, and
toluene (Table 1, entries 2, and 7e9). Finally, the suitable reaction
temperature and time were determined to be 25 ꢀC and 3 h (Table 1,
entries 2, and 10e13).
a
Reaction conditions: Compound
1
(0.6 mmol),
2
(0.5 mmol), Yb(OTf)3
(0.05 mmol), solvent (5 mL).
b
Isolated yields refer to 2.
Run at reflux.
nd¼No desired product detected.
c
d
on the propargyl alcohols, reactions proceeded smoothly (Table 2,
entries 1e6). Propargyl alcohols 1e and 1f, with the electron-
withdrawing group substituted, could not be completely con-
sumed at room temperature. Fortunately, by raising the reaction
temperature, 3e and 3f could be obtained in 86% and 95% yields,
respectively (Table 2, entries 5 and 6). When 2,4-diphenylbut-3-yn-
2-ol (1g) was used as the substrate, no desired product was ob-
tained (Table 2, entry 7) as 1g was consumed completely. In cases of
various substituents on R3 (Table 2, entries 8e12), groups with the
nature of the electron-withdrawing (1jel, Table 2, entries 8e10)
increased the yields in comparison with the electron-donating
groups (1h, 1i, Table 2, entries 11 and 12), while the sterically
hindered 3-(2-bromophenyl)-1,1-diphenylprop-2-yn-1-ol (1m)
gave relatively lower yield (Table 2, entry 13). Aliphatic alkyne 1n
could also afford the desired product 3n in 46% yield (Table 2, entry
14). However, terminal alkyne 1o failed to afford the desired
product 3o (Table 2, entry 15). TMS substituted alkyne 1p could
afford the desired product 3p in 46% yield (Table 2, entry 16), but
attempt to remove TMS for generation of 3o by using KF$2H2O
failed and the decomposition of 3p occurred to yield
benzophenone.
Screening of the reaction conditions for the formation of 4a was
summarized in Table S1. The best yield was obtained by mixing 1a
(0.6 mmol), 2 (0.5 mmol), and iodine (1.0 mmol) in wet DCM (5 mL)
and reacting at room temperature for 4 h. With this procedure, we
prepared various 4-iodo-2,5-dihydroisoxazoles 4aen as depicted in
Table 3. The reaction could tolerate both electron-donating (Table 3,
entries 1e4 and 7e9) and electron-withdrawing groups (Table 3,
entries 5, 6 and 10e13). Aliphatic alkyne 1n afforded 4n in 35%
yield (Table 3, entry 14). It is noteworthy that 2,4-diphenylbut-3-
yn-2-ol (1g) could work to give the desired product 4g in 27%
yield (Table 3, entry 7). However, terminal alkyne 1o also did not
yield the desired product (Table 3, entry 15).
Table 1
Screening the reaction conditions for the formation of 3aa
Entry
Catalyst
Temp (ꢀC)
Time
Solvent
Yieldb (%)
1
2
3
4
5
6
7
8
BF3$Et2Oc
Yb(OTf)3
AgOTf
Cu(OTf)2
HOTf
TsOH$H2O
Yb(OTf)3
Yb(OTf)3
Yb(OTf)3
Yb(OTf)3
Yb(OTf)3
Yb(OTf)3
Yb(OTf)3
25
25
25
25
25
25
25
25
25
25
25
Reflux
0
15 min
3 h
30 min
6 h
15 min
2 h
6 h
3 h
56 h
2 h
4 h
1 h
DCM
DCM
DCM
DCM
DCM
DCM
DCE
MeCN
Toluene
DCM
DCM
DCM
DCM
54
82
65
57
50
75
78
15
81
67
81
73
82
9
10
11
12
13
36 h
a
Reaction conditions: Compound 1a (0.6 mmol),
2 (0.5 mmol), catalyst
(0.05 mmol), solvent (5 mL).
b
Isolated yield referred to 2.
Catalyst (0.6 mmol) used.
c
With the optimized reaction conditions in hand, we sub-
sequently tested the substrate diversity for this transformation. As
shown in Table 2, the triaryl substituted propargyl alcohols 1aef
(Table 2, entries 1e6) and 1hem (Table 2, entries 8e13) and the
diaryl substituted propargyl alcohol 1n (Table 2, entry 14) could
undergo this cascade process to afford the corresponding 2,5-
dihydroisoxazoles 3ae3f, 3he3n and 3p in moderate to excellent
yields (30e95%). With different aryl groups (R1, R2, 1aef) occupied
We also examined the secondary propargylic alcohol 1q
(Scheme 3). In this case, however, a direct N-propynylation of N-
tosyl hydroxylamine occurred to form 5 in 38% yield. This result is
similar to Campagne’s work.10

10196
Y. Zhu et al. / Tetrahedron 68 (2012) 10194e10200
Table 3
Tandem synthesis of 4a
1 (R1/R2/R3)
Time (h)
Product/yieldb (%)
Scheme 5. Formation of 4-bromo-2,5-dihydroisoxazoles.
Entry
1
2
3
4
5
6
7
8
1a (Ph/Ph/Ph)
4
2
4
4a/53
4b/41
4c/47
4d/52
4e/56c
4f/63c
4g/27
4h/31
4i/52
4j/64
4k/67
4l/71
4m/59
4n/35
ndd
1b (4-MeOC6H4/4-MeOC6H4/Ph)
1c (4-MeC6H4/4-MeC6H4/Ph)
1d (4-MeC6H4/Ph/Ph)
1e (4-ClC6H4/Ph/Ph)
1f (4-ClC6H4/4-ClC6H4/Ph)
1g (Ph/Me/Ph)
1h (Ph/Ph/4-MeOC6H4)
1i (Ph/Ph/4-MeC6H4)
1j (Ph/Ph/4-FC6H4)
1k (Ph/Ph/4-BrC6H4)
1l (Ph/Ph/3-BrC6H4)
1m (Ph/Ph/2-BrC6H4)
1n (Ph/Ph/n-Bu)
4
more stable than the resonance structure B when R¼Ph, while B is
more stable than Awhen R¼H.12 Attributed to the tosyl group on the
hydroxylamine, nitrogen presented stronger nucleophilicity than
oxygen did.13 As a result, N-sulfonylallenamide C14 and 5 can be
obtained by trapping A and B with N-sulfonyl hydroxylamine, re-
spectively. In the presence of different electrophiles, such as Hþ, Iþ,
or Brþ, the active N-sulfonylallenamide C is further converted into
isolable 3a, 4a, or 6a in a cascade way. In the cases where I2 was used
as electrophile (Table 3), additional Lewis acid was not necessary
because molecular iodine is actually a well known Lewis acid.8c,15
12
20
2
4
4
4
5
4
4
9
10
11
12
13
14
15
3
4
1o (Ph/Ph/H)
a
Reaction conditions: Compound 1 (0.6 mmol), 2 (0.5 mmol), I2 (1.0 mmol),
solvent (5 mL).
b
c
Isolated yields refer to 2.
Run at reflux.
nd¼No desired product detected.
d
Scheme 3. Synthesis of N-propargyl hydroxylamine 5.
In order to test the scalability and to demonstrate the practical
utilities of these two tandem transformations, reactions were per-
formed on gram scale. As shown in Scheme 4, reactions proceeded
well to afford 3a (1.43 g, 79% yield) and 4a (1.04 g, 45% yield),
respectively.
Scheme 6. Proposed mechanism for the tandem transformation.
As aryl halide is an important family in transition metal cata-
lyzed coupling reactions, we tested 4-iodo-2,5-dihydroisoxazoles
for palladium catalyzed carbonylation.16 Thus, 4a, 4c, and 4d
were, respectively, loaded in autoclave (Scheme 7). To our sur-
prising, 7a, 7b, and 7c were constructed in moderate yields. It
Scheme 4. Reactions on gram scale.
This protocol could also be used to prepare 4-bromo-2,5-
dihydroisoxazoles 6aec (Scheme 5) with the combination of NBS
and ytterbium triflate.
On the basis of the aforementioned experiments, a plausible
mechanism is outlined in Scheme 6. Cooperated with Lewis acid, 1
can undergo a MeyereSchuster rearrangement11 to form allenic
carbocation A (R¼Ph) or a direct dehydration to generate prop-
argylic carbocation B (R¼H), depending on the pendant group R.
According to theoretical calculation, the resonance structure A is
Scheme 7. Further elaboration of compounds 4.

Y. Zhu et al. / Tetrahedron 68 (2012) 10194e10200
10197
indicated that the palladium catalyzed carbonylation occurred in
accompany with the detosylation. Besides, the constructed 4-
methoxycarbonyl-4,5-dihydroisoxazole is the subunit of bi-
ologically active compounds.17
(m, 2H), 6.94 (d, J¼8.5 Hz, 4H), 6.85 (d, J¼8.0 Hz, 2H), 6.70 (d,
J¼8.5 Hz, 4H), 5.65 (s, 1H), 3.78 (s, 6H), 2.33 (s, 3H); 13C NMR
(125 MHz, CDCl3):
d 159.2, 144.8, 141.4, 136.8, 130.3, 130.2, 129.9,
129.4, 129.0, 128.4, 128.3, 128.2, 117.5, 113.6, 95.3, 55.5, 21.9; IR
(film): 2929, 1608, 1510, 1364, 1251, 1168, 1031 cmꢁ1; MS (ESI) m/z
([MþH]þ): 514; HRMS (EI) calcd for C30H27NO5S: 513.1610; found:
513.1625.
3. Conclusions
In conclusion, we have developed an efficient protocol for the
preparation of 2,5-dihydroisoxazoles and 4-halo-2,5-dihydro-
isoxazoles from readily available and simple starting materials.
Moreover, the resulting 4-iodo-2,5-dihydroisoxazoles could be
converted into 4-methoxycarbonyl-4,5-dihydroisoxazoles via pal-
ladium catalyzed carbonylation and detosylation. Further re-
searches on the chemistry of allenamide are ongoing in our
laboratory.
4.2.3. 3-Phenyl-5,5-di-p-tolyl-2-tosyl-2,5-dihydroisoxazole
White solid (168 mg, 70%), mp 106e108 ꢀC; 1H NMR (500 MHz,
CDCl3):
(3c).
d
7.68e7.62 (m, 2H), 7.43e7.35 (m, 3H), 7.21 (d, J¼8.0 Hz,
2H), 6.97 (d, J¼8.0 Hz, 4H), 6.91 (d, J¼8.0 Hz, 4H), 6.79 (d, J¼8.0 Hz,
2H), 5.67 (s, 1H), 2.33e2.29 (m, 9H); 13C NMR (125 MHz, CDCl3):
d
144.8, 141.6, 141.5, 137.4, 130.3, 130.2, 129.9, 129.2, 129.0, 128.9,
128.4, 128.3, 126.7, 117.3, 95.6, 21.9, 21.3; IR (film): 2917, 1596, 1506,
1367, 1171, 1049 cmꢁ1; MS (ESI) m/z ([MþH]þ): 482; HRMS (EI)
calcd for C30H27NO3S: 481.1712; found: 481.1724.
4. Experimental section
4.1. General
4.2.4. 3,5-Diphenyl-5-(p-tolyl)-2-tosyl-2,5-dihydroisoxazole
(3d). White solid (189 mg, 81%), mp 163e164 ꢀC; 1H NMR
1H NMR spectra were recorded on 500 MHz or 400 MHz
spectrometer. The chemical shifts were reported relative to in-
ternal standard TMS (0 ppm) in CDCl3. The following abbreviations
were used to describe peak patterns where appropriate: b¼broad,
s¼singlet, d¼doublet, t¼triplet, q¼quartet, m¼multiplet. Coupling
constants were reported in hertz (Hz). 13C NMR were recorded on
125 MHz or 100 MHz and referenced to the internal solvent sig-
nals (77.27 ppm for CDCl3). Infrared spectra were obtained on an
FTIR spectrometer. Low-resolution MS were obtained by ESI ioni-
zation. high-resolution mass spectra (HRMS) data were obtained
by using ESI ionization on ion cyclotron resonance (ICR) mass
spectrometer or EI ionization on time-of-flight (TOF) mass spec-
trometer. Melting points were measured with micro melting point
apparatus.
(500 MHz, CDCl3): d 7.68e7.62 (m, 2H), 7.45e7.37 (m, 3H),
7.24e7.14 (m, 5H), 7.08e7.02 (m, 2H), 6.98 (d, J¼8.0 Hz, 2H), 6.90 (d,
J¼8.0 Hz, 2H), 6.80 (d, J¼8.0 Hz, 2H), 5.69 (s, 1H), 2.32 (s, 6H); 13C
NMR (125 MHz, CDCl3):
d 144.8, 144.5, 141.7, 141.5, 137.4, 130.3,
130.2, 129.9, 129.00,128.99,128.4, 128.3,128.3, 127.6,126.74,126.71,
117.1, 95.6, 21.9, 21.3; IR (film): 1593, 1489, 1444, 1364, 1168,
1087 cmꢁ1; MS (ESI) m/z ([MþH]þ): 468; HRMS (EI) calcd for
C29H25NO3S: 467.1555; found: 467.1559.
4.2.5. 5-(4-Chlorophenyl)-3,5-diphenyl-2-tosyl-2,5-dihydro-iso-
xazole (3e). White solid (210 mg, 86%); mp 166e167 ꢀC; 1H NMR
(500 MHz, CDCl3): d 7.70e7.62 (m, 2H), 7.45e7.37 (m, 3H), 7.24e7.18
(m, 5H), 7.14 (d, J¼8.5 Hz, 2H), 7.08e7.02 (m, 2H), 6.95 (d, J¼8.5 Hz,
2H), 6.84 (d, J¼8.0 Hz, 2H), 5.66 (s, 1H), 2.35 (s, 3H); 13C NMR
CH2Cl2, MeCN, and 1,2-dichloroethane were distilled from
CaH2. The propargyl alcohols18 and N-tosyl hydroxylamine19 were
prepared according to the published methods. 1,1-Diphenylprop-
2-yn-1-ol (1o) and other materials were purchased from common
commercial sources and used without additional purification.
(125 MHz, CDCl3): d 145.3, 143.8, 142.9, 142.2, 133.7, 130.18, 130.15,
130.0, 129.1, 128.9, 128.53, 128.50, 128.3, 128.2, 127.9, 126.6, 116.2,
95.1, 21.9; IR (film): 3060, 1596, 1489, 1367, 1174, 1087 cmꢁ1; MS
(ESI) m/z ([MþH]þ): 488; HRMS (EI) calcd for C28H22ClNO3S:
487.1009; found: 487.1004.
4.2. General procedure for the synthesis of 3
4.2.6. 5,5-Bis(4-chlorophenyl)-3-phenyl-2-tosyl-2,5-dihydro-iso-
xazole (3f). White solid (248 mg, 95%); mp 111e113 ꢀC; 1H NMR
To a solution of propargyl alcohol 1 (0.6 mmol) and N-tosyl
hydroxylamine 2 (0.5 mmol) in dry DCM (5 mL) was added
Yb(OTf)3 (0.05 mmol) slowly at 25 ꢀC, and the reaction mixture
was stirred at the shown temperature for an indicated period of
time shown in text. Saturated aqueous brine was added to quench
the reaction and the mixture was extracted with DCM. The or-
ganic layer was washed with brine and dried over Na2SO4, filtered
and concentrated. The residue was purified by flash column
chromatography on silica gel with DCM/hexane as eluent to
give 3.
(500 MHz, CDCl3): d 7.68e7.62 (m, 2H), 7.45e7.40 (m, 3H), 7.22
(d, J¼8.5 Hz, 2H), 7.16 (d, J¼8.5 Hz, 4H), 6.96 (d, J¼9.0 Hz, 4H),
6.88 (d, J¼8.0 Hz, 2H), 5.62 (s, 1H), 2.38 (s, 3H); 13C NMR
(125 MHz, CDCl3):
d 145.6, 142.6, 142.4, 134.0, 130.3, 130.2, 129.7,
129.1, 129.0, 128.7, 128.6, 128.3, 128.2, 115.5, 94.6, 21.9; IR (film):
2922, 1593, 1489, 1367, 1168, 1090, 814 cmꢁ1; MS (EI) m/z
([MꢁTs]þ): 366; HRMS (EI) calcd for C28H21Cl2NO3S: 521.0619;
found: 521.0623.
4.2.7. 3-(4-Methoxyphenyl)-5,5-diphenyl-2-tosyl-2,5-dihydro-iso-
xazole (3h). White solid (104 mg, 43%); mp 134e138 ꢀC; 1H NMR
4.2.1. 3,5,5-Triphenyl-2-tosyl-2,5-dihydroisoxazole (3a). White solid
(186 mg, 82%); mp 183e184 ꢀC; 1H NMR (500 MHz, CDCl3):
(500 MHz, CDCl3):
d
7.60 (d, J¼8.5 Hz, 2H), 7.23e7.14 (m, 8H),
7.07e7.00 (m, 4H), 6.93 (d, J¼8.0 Hz, 2H), 6.79 (d, J¼8.0 Hz, 2H),
d
7.70e7.62 (m, 2H), 7.43e7.37 (m, 3H), 7.24e7.15 (m, 8H),
7.07e7.00 (m, 4H), 6.79 (d, J¼8.0 Hz, 2H), 5.70 (s, 1H), 2.30 (s, 3H);
13C NMR (125 MHz, CDCl3):
144.9, 144.3, 141.8, 130.2, 130.0, 129.1,
5.60 (s, 1H), 3.84 (s, 3H), 2.31 (s, 3H); 13C NMR (125 MHz, CDCl3):
d
160.1, 144.8, 144.5, 141.5, 130.2, 129.7, 129.1, 129.0, 128.3, 127.6,
d
126.8, 122.4, 115.1, 113.9, 95.5, 55.6, 21.9; IR (film): 2920, 1608,
1507, 1367, 1257, 1171, 1046 cmꢁ1; MS (ESI) m/z ([MþNa]þ): 506;
HRMS (EI) calcd for C29H25NO4S: 483.1504; found: 483.1503.
128.9, 128.5, 128.4, 128.3, 127.7, 126.8, 116.9, 95.6, 21.9; IR (film):
3056, 2922, 1596, 1489, 1364, 1168, 1049 cmꢁ1; MS (ESI) m/z
([MþH]þ): 454; HRMS (EI) calcd for C28H23NO3S: 453.1399; found:
453.1398.
4.2.8. 5,5-Diphenyl-3-(p-tolyl)-2-tosyl-2,5-dihydroisoxazole
(3i).
White solid (129 mg, 55%); mp 148e149 ꢀC; 1H NMR (500 MHz,
4.2.2. 5,5-Bis(4-methoxyphenyl)-3-phenyl-2-tosyl-2,5-dihydro-iso-
CDCl3):
d
7.55 (d, J¼7.5 Hz, 2H), 7.25e7.14 (m, 10H), 7.08e7.00 (m,
xazole (3b). White solid (146 mg, 57%); mp 93e95 ꢀC; 1H NMR
4H), 6.79 (d, J¼8.0 Hz, 2H), 5.65 (s, 1H), 2.38 (s, 3H), 2.30 (s, 3H); 13C
(500 MHz, CDCl3):
d
7.70e7.62 (m, 2H), 7.43e7.37 (m, 3H), 7.26e7.20
NMR (125 MHz, CDCl3): d 144.8, 144.4, 141.9, 140.1, 130.2, 129.2,

10198
Y. Zhu et al. / Tetrahedron 68 (2012) 10194e10200
129.1, 129.0, 128.3, 128.2, 127.6, 127.3, 126.8, 116.0, 95.5, 21.9, 21.7; IR
(film): 3051, 3027, 1596, 1489, 1450, 1367, 1168, 1046 cmꢁ1; MS (ESI)
m/z ([MþNa]þ): 490; HRMS (EI) calcd for C29H25NO3S: 467.1555;
found: 467.1563.
([MþH]þ): 450; HRMS (EI) calcd for C25H27NO3SSi: 449.1481;
found: 449.1481.
4.3. General procedure for the synthesis of 4 and 5
4.2.9. 3-(4-Fluorophenyl)-5,5-diphenyl-2-tosyl-2,5-dihydro-iso-
To a solution of propargyl alcohol 1 (0.6 mmol) and N-tosyl
hydroxylamine 2 (0.5 mmol) in wet DCM (5 mL) was added I2
(1.0 mmol) slowly at 25 ꢀC, and the reaction mixture was stirred at
a shown temperature for an indicated period of time shown in text.
Saturated aqueous Na2S2O3 was added to quench the reaction and
the mixture was extracted with DCM. The organic layer was washed
with brine and dried over Na2SO4, filtered and concentrated. The
residue was purified flash column chromatography on silica gel
with DCM/hexane as eluent to give 4 or 5.
xazole (3j). White solid (203 mg, 86%); mp 158e159 ꢀC; 1H NMR
(500 MHz, CDCl3):
d 7.68e7.60 (m, 2H), 7.25e7.16 (m, 8H), 7.10 (t,
J¼8.5 Hz, 2H), 7.05e7.00 (m, 4H), 6.80 (d, J¼8.0 Hz, 2H), 5.67 (s,
1H), 2.31 (s, 3H); 13C NMR (125 MHz, CDCl3):
d 163.7 (d,
1JCF¼248 Hz), 145.0, 144.3, 140.8, 130.22, 130.16, 129.2, 128.9, 128.4,
2
127.7, 126.7, 126.3, 116.6, 115.6 (d, JCF¼22 Hz), 95.7, 21.9; IR (film):
2917, 1650, 1601, 1504, 1364, 1171, 1049 cmꢁ1; MS (ESI) m/z
([MþNa]þ): 494; HRMS (EI) calcd for C28H22FNO3S: 471.1304;
found: 471.1320.
4.3.1. 4-Iodo-3,5,5-triphenyl-2-tosyl-2,5-dihydroisoxazole
(4a).
4.2.10. 3-(4-Bromophenyl)-5,5-diphenyl-2-tosyl-2,5-dihydro-iso-
White solid (153 mg, 53%); mp 185e186 ꢀC; 1H NMR (500 MHz,
xazole (3k). White solid (226 mg, 85%); mp 169e170 ꢀC; 1H NMR
CDCl3): d 7.78e7.70 (m, 2H), 7.53e7.43 (m, 3H), 7.30e7.18 (m, 8H),
(500 MHz, CDCl3):
d
7.57e7.50 (m, 4H), 7.22e7.13 (m, 8H), 7.02 (d,
7.17e7.12 (m, 4H), 6.89 (d, J¼8.5 Hz, 2H), 2.38 (s, 3H); 13C NMR
J¼6.5 Hz, 4H), 6.80 (d, J¼7.0 Hz, 2H), 5.72 (s, 1H), 2.31 (s, 3H); 13C
(125 MHz, CDCl3): d 145.1, 143.1, 142.3, 130.4, 130.3, 130.0, 129.8,
NMR (125 MHz, CDCl3):
d
145.1, 144.1, 140.8, 131.7, 130.1, 129.7,
129.5, 128.7, 128.3, 128.2, 128.0, 98.1, 82.7, 22.0; IR (film): 3054,
1596, 1492, 1444, 1367, 1174, 1084 cmꢁ1; MS (ESI) m/z ([MþH]þ):
580; HRMS (EI) calcd for C28H22INO3S: 579.0365; found: 579.0363.
129.2, 129.1, 128.7, 128.4, 127.8, 126.7, 124.2, 117.3, 95.8, 21.9; IR
(film): 3060, 2920,1650,1596,1489,1364,1171,1046 cmꢁ1; MS (ESI)
m/z ([MþNa]þ): 554; HRMS (EI) calcd for C28H22BrNO3S: 531.0504;
found: 531.0508.
4.3.2. 4-Iodo-5,5-bis(4-methoxyphenyl)-3-phenyl-2-tosyl-2,5-
dihydroisoxazole (4b). White solid (131 mg, 41%), mp 184e185 ꢀC;
4.2.11. 3-(3-Bromophenyl)-5,5-diphenyl-2-tosyl-2,5-dihydro-iso-
1H NMR (500 MHz, CDCl3):
d 7.76e7.70 (m, 2H), 7.50e7.43 (m, 3H),
xazole (3l). Pale gray solid (218 mg, 82%); mp 183e184 ꢀC; 1H NMR
7.30e7.22 (m, 2H), 7.07 (d, J¼9.0 Hz, 4H), 6.93 (d, J¼8.0 Hz, 2H), 6.72
(500 MHz, CDCl3):
d
7.77e7.74 (m, 1H), 7.62 (d, J¼8.0 Hz, 1H),
(d, J¼9.0 Hz, 4H), 3.81 (s, 6H), 2.40 (s, 3H); 13C NMR (125 MHz,
7.54e7.50 (m, 1H), 7.31e7.26 (m, 1H), 7.25e7.15 (m, 8H), 7.07e6.98
(m, 4H), 6.82 (d, J¼8.0 Hz, 2H), 5.75 (s, 1H), 2.32 (s, 3H); 13C NMR
CDCl3): d 159.6, 145.1, 142.6, 134.6, 130.34, 130.31, 130.2, 130.1, 130.0,
129.4, 128.3, 113.3, 98.0, 84.0, 55.5, 22.0; IR (film): 1608, 1513, 1373,
1257, 1174, 1087, 1034 cmꢁ1; MS (ESI) m/z ([MþH]þ): 640; HRMS
(EI) calcd for C30H26INO5S: 639.0576; found: 639.0566.
(125 MHz, CDCl3):
d 145.1, 144.0, 140.4, 132.9, 132.2, 130.8, 130.2,
130.0, 129.2, 128.7, 128.4, 127.8, 127.1, 126.7, 122.4, 118.0, 95.8, 21.9;
IR (film): 3062, 3021, 1595, 1561, 1491, 1366, 1172, 1088, 1050 cmꢁ1
;
MS (ESI) m/z ([MþH]þ): 532; HRMS (EI) calcd for C28H22BrNO3S:
4.3.3. 4-Iodo-3-phenyl-5,5-di-p-tolyl-2-tosyl-2,5-dihydro-isoxazole
531.0504; found: 531.0502.
(4c). White solid (143 mg, 47%); mp 172e173 ꢀC; 1H NMR
(500 MHz, CDCl3):
J¼8.0 Hz, 2H), 7.06e6.96 (m, 8H), 6.89 (d, J¼8.5 Hz, 2H), 2.39 (s, 3H),
2.34 (s, 6H); 13C NMR (125 MHz, CDCl3):
145.1, 142.7, 139.5, 138.0,
d 7.77e7.70 (m, 2H), 7.50e7.43 (m, 3H), 7.24 (d,
4.2.12. 3-(2-Bromophenyl)-5,5-diphenyl-2-tosyl-2,5-dihydro-iso-
xazole (3m). White solid (80 mg, 30%); mp 169e172 ꢀC; 1H NMR
d
(500 MHz, CDCl3):
d
7.81 (dd, J¼7.5, 1.5 Hz, 1H), 7.66 (d, J¼8.0 Hz,
130.3, 130.2, 130.1, 129.9, 129.3, 128.6, 128.3, 98.2, 83.4, 22.0, 21.4; IR
(film): 3030, 1590, 1513, 1447, 1367, 1168, 1087 cmꢁ1; MS (ESI) m/z
([MþH]þ): 608; HRMS (EI) calcd for C30H26INO3S: 607.0678; found:
607.0670.
1H), 7.40e7.31 (m, 3H), 7.25e7.15 (m, 7H), 7.10e7.04 (m, 4H), 6.82
(d, J¼8.0 Hz, 2H), 6.05 (s, 1H), 2.32 (s, 3H); 13C NMR (125 MHz,
CDCl3):
d 145.0, 144.1, 137.9, 134.0, 132.6, 130.7, 130.6, 130.4, 129.2,
129.0, 128.4, 127.8, 127.3, 127.0, 121.7, 120.6, 96.8, 21.9; IR (film):
3057, 3027, 1653, 1593, 1367, 1170, 1087 cmꢁ1; MS (ESI) m/z
([MþH]þ): 532; HRMS (EI) calcd for C28H22BrNO3S: 531.0504;
found: 531.0508.
4.3.4. 4-Iodo-3,5-diphenyl-5-(p-tolyl)-2-tosyl-2,5-dihydro-isoxazole
(4d). White solid (154 mg, 52%); mp 160e161 ꢀC (decomposition);
1H NMR (500 MHz, CDCl3):
d 7.77e7.71 (m, 2H), 7.52e7.44 (m, 3H),
7.30e7.18 (m, 5H), 7.16 (d, J¼7.5 Hz, 2H), 7.05e6.97 (m, 4H), 6.89 (d,
4.2.13. 3-Butyl-5,5-diphenyl-2-tosyl-2,5-dihydroisoxazole
White solid (100 mg, 46%); mp 106e107 ꢀC; 1H NMR (500 MHz,
CDCl3):
(3n).
J¼8.0 Hz, 2H), 2.39 (s, 3H), 2.36 (s, 3H); 13C NMR (125 MHz, CDCl3):
d
145.1, 142.9, 142.4, 139.4, 138.1, 130.4, 130.3, 130.0, 129.4, 128.75,
d
7.37 (d, J¼8.5 Hz, 2H), 7.22e7.16 (m, 6H), 6.97 (d,
128.68, 128.6, 128.3, 128.2, 127.9, 98.2, 83.1, 22.0, 21.5; IR (film):
1596, 1489, 1447, 1373, 1174, 1087 cmꢁ1; MS (ESI) m/z ([MþH]þ):
594; HRMS (EI) calcd for C29H24INO3S: 593.0522; found: 593.0528.
J¼7.5 Hz, 4H), 6.83 (d, J¼8.5 Hz, 2H), 5.36 (s, 1H), 2.60 (t, J¼8.0 Hz,
2H), 2.31 (s, 3H), 1.70e1.60 (m, 2H), 1.43e1.32 (m, 2H), 0.92 (t,
J¼7.5 Hz, 3H); 13C NMR (125 MHz, CDCl3):
d 144.8, 144.5, 141.4,
129.8, 129.4, 129.2, 128.2, 127.5, 126.8, 114.9, 94.8, 30.1, 27.8, 22.5,
21.8, 14.0; IR (film): 1596, 1489, 1447, 1364, 1174, 1087 cmꢁ1; MS
(ESI) m/z ([MþK]þ): 472; HRMS (EI) calcd for C26H27NO3S:
433.1712; found: 433.1717.
4.3.5. 5-(4-Chlorophenyl)-4-iodo-3,5-diphenyl-2-tosyl-2,5-
dihydroisoxazole (4e). White solid (172 mg, 56%); mp 173e174 ꢀC;
1H NMR (500 MHz, CDCl3):
d 7.77e7.70 (m, 2H), 7.52e7.44 (m, 3H),
7.32e7.20 (m, 5H), 7.20e7.12 (m, 4H), 7.07 (d, J¼8.5 Hz, 2H), 6.93 (d,
J¼8.0 Hz, 2H), 2.42 (s, 3H); 13C NMR (125 MHz, CDCl3):
d 145.5,
4.2.14. 5,5-Diphenyl-2-tosyl-3-(trimethylsilyl)-2,5-dihydroisoxazole
143.4, 141.9, 141.0, 134.4, 130.6, 130.2, 130.0, 129.94, 129.91, 129.5,
128.7,128.5,128.4,128.3,128.1, 97.7, 81.9, 22.0; IR (film): 3056,1602,
1486, 1444, 1373, 1171, 1093 cmꢁ1; MS (ESI) m/z ([MþH]þ): 614;
HRMS (EI) calcd for C28H21ClINO3S: 612.9975; found: 612.9969.
(3p). White solid (103 mg, 46%); mp 131e133 ꢀC; 1H NMR
(400 MHz, CDCl3):
(d, J¼7.6 Hz, 4H), 6.83 (d, J¼8.0 Hz, 2H), 5.73 (s, 1H), 2.28 (s, 3H),
0.39 (s, 9H); 13C NMR (100 MHz, CDCl3):
144.6, 144.3, 141.5, 130.1,
d
7.44 (d, J¼7.6 Hz, 2H), 7.22e7.10 (m, 6H), 6.96
d
129.9, 129.7, 129.1, 128.3, 127.4, 126.9, 95.4, 21.8, 0.02; IR (film):
3054, 1593, 1492, 1447, 1355, 1168, 1084 cmꢁ1; MS (ESI) m/z
4.3.6. 5,5-Bis(4-chlorophenyl)-4-iodo-3-phenyl-2-tosyl-2,5-dihydro-
isoxazole (4f). White solid (204 mg, 63%); mp 189e190 ꢀC; 1H NMR

Y. Zhu et al. / Tetrahedron 68 (2012) 10194e10200
10199
(500 MHz, CDCl3):
d
7.76e7.70 (m, 2H), 7.52e7.45 (m, 3H),
129.65, 128.9, 128.7, 128.4, 128.1, 122.2, 98.4, 84.0, 22.0; IR (film):
3063, 1596, 1492, 1447, 1370, 1170, 1087 cmꢁ1; MS (ESI) m/z
([MþH]þ): 658; HRMS (EI) calcd for C28H21BrINO3S: 656.9470;
found: 656.9473.
7.27e7.22 (m, 2H), 7.20e7.15 (m, 4H), 7.10e7.03 (m, 4H), 6.96 (d,
J¼8.0 Hz, 2H), 2.44 (s, 3H); 13C NMR (125 MHz, CDCl3):
d 145.9,
143.7, 140.5, 134.7, 130.7, 130.2, 129.93, 129.89, 129.8, 129.5, 128.45,
128.38, 97.2, 81.0, 22.0; IR (film): 3069, 1596, 1489, 1370, 1171, 1093,
1010 cmꢁ1; MS (ESI) m/z ([MþNa]þ): 670; HRMS (EI) calcd for
C28H20Cl2INO3S: 646.9586; found: 646.9599.
4.3.13. 3-(2-Bromophenyl)-4-iodo-5,5-diphenyl-2-tosyl-2,5-
dihydroisoxazole (4m). White solid (194 mg, 59%); mp 177e178 ꢀC;
1H NMR (500 MHz, CDCl3):
d
7.68 (d, J¼8.0 Hz, 1H), 7.58e7.52 (m,
1H), 7.47e7.40 (m, 3H), 7.35e7.16 (m, 11H), 6.89 (d, J¼8.0 Hz, 2H),
2.35 (s, 3H); 13C NMR (125 MHz, CDCl3):
145.2, 142.3, 142.05,
4.3.7. 4-Iodo-5-methyl-3,5-diphenyl-2-tosyl-2,5-dihydroisoxazole
(4g). White solid (70 mg, 27%); mp 151e152 ꢀC (decomposition);
d
1H NMR (500 MHz, CDCl3):
d
7.72e7.65 (m, 2H), 7.56 (d, J¼8.0 Hz,
2H), 7.50e7.42 (m, 3H), 7.32e7.23 (m, 5H), 7.21 (d, J¼8.0 Hz, 2H),
2.44 (s, 3H), 1.60 (s, 3H); 13C NMR (125 MHz, CDCl3):
145.6, 141.9,
142.00, 133.9, 133.0, 131.7, 131.5, 130.7, 130.2, 129.3, 129.0, 128.9,
128.38, 128.35, 128.1, 128.0, 127.3, 123.4, 98.5, 86.7, 21.9; IR (film):
3057, 1593, 1492, 1447, 1373, 1174, 1084 cmꢁ1; MS (ESI) m/z
([MþNa]þ): 680; HRMS (EI) calcd for C28H21BrINO3S: 656.9470;
found: 656.9469.
d
141.3, 130.9, 130.3, 130.2, 130.0, 129.9, 129.7, 128.5, 128.4, 128.3,
127.0, 95.4, 85.0, 25.9, 22.0; IR (film): 3060, 1593, 1495, 1450, 1370,
1171, 1087 cmꢁ1; MS (ESI) m/z ([MþNa]þ): 540; HRMS (EI) calcd for
C23H20INO3S: 517.0209; found: 517.0200.
4.3.14. 3-Butyl-4-iodo-5,5-diphenyl-2-tosyl-2,5-dihydroisoxazole
(4n). White solid (98 mg, 35%), mp 148e149 ꢀC; 1H NMR
4.3.8. 4-Iodo-3-(4-methoxyphenyl)-5,5-diphenyl-2-tosyl-2,5-
(500 MHz, CDCl3):
d
7.34 (d, J¼8.0 Hz, 2H), 7.28e7.21 (m, 2H), 7.16
dihydroisoxazole (4h). White solid (94 mg, 31%); mp 177e178 ꢀC;
(t, J¼7.5 Hz, 4H), 7.02 (d, J¼8.0 Hz, 4H), 6.91 (d, J¼8.0 Hz, 2H), 2.84
1H NMR (500 MHz, CDCl3):
d 7.73e7.67 (m, 2H), 7.30e7.25 (m,
(t, J¼7.5 Hz, 2H), 2.37 (s, 3H), 1.80e1.70 (m, 2H), 1.42e1.32 (m, 2H),
2H), 7.24e7.17 (m, 6H), 7.15e7.10 (m, 4H), 7.00 (d, J¼9.0 Hz, 2H),
0.95 (t, J¼7.5 Hz, 3H); 13C NMR (125 MHz, CDCl3):
d 144.9, 143.4,
6.88 (d, J¼8.0 Hz, 2H), 3.87 (s, 3H), 2.38 (s, 3H); 13C NMR
141.9, 129.6, 129.5, 129.4, 128.3, 127.8, 127.7, 96.1, 82.5, 29.8, 29.7,
22.1, 21.7,13.9; IR (film): 1599,1489,1447,1367,1171,1087 cmꢁ1; MS
(ESI) m/z ([MþH]þ): 560; HRMS (EI) calcd for C26H26INO3S:
559.0678; found: 559.0677.
(125 MHz, CDCl3):
d 161.2, 145.0, 142.9, 142.5, 131.8, 129.9, 129.5,
128.7, 128.2, 128.0, 122.1, 113.7, 97.9, 81.2, 55.6, 22.0; IR (film):
3060, 1608, 1510, 1447, 1373, 1257, 1174, 1087 cmꢁ1; MS (ESI) m/z
([MþH]þ): 610; HRMS (EI) calcd for C29H24INO4S: 609.0471;
found: 609.0473.
4.3.15. N-(1,3-Diphenylprop-2-yn-1-yl)-N-hydroxy-4-methylbenze-
nesulfonamide (5). White solid (72 mg, 38%); mp 113e114 ꢀC; 1H
4.3.9. 4-Iodo-5,5-diphenyl-3-(p-tolyl)-2-tosyl-2,5-dihydroisoxazole
NMR (500 MHz, CDCl3):
2H), 7.40e7.17 (m, 8H), 7.05 (d, J¼7.5 Hz, 2H), 6.32 (s, 1H), 5.99 (s,
1H), 2.22 (s, 3H); 13C NMR (125 MHz, CDCl3):
145.2, 136.2, 131.9,
131.8, 130.2, 129.6, 128.77, 128.75, 128.70, 128.68, 128.2, 122.3, 89.1,
81.6, 57.4, 21.7; IR (film): 3378, 3066, 1599, 1486, 1346, 1168,
1087 cmꢁ1; MS (ESI) m/z ([MþK]þ): 416; HRMS (ESI) calcd for
C22H19NO3SNa: 400.0980; found: 400.0971.
d
7.90 (d, J¼8.5 Hz, 2H), 7.63 (d, J¼7.5 Hz,
(4i). White solid (154 mg, 52%); mp 174e175 ꢀC; 1H NMR
(500 MHz, CDCl3):
7.15e7.10 (m, 4H), 6.88 (d, J¼8.0 Hz, 2H), 2.42 (s, 3H), 2.38 (s, 3H);
13C NMR (125 MHz, CDCl3):
145.0, 143.2, 142.4, 140.7, 130.2, 130.0,
129.8, 129.5, 129.1, 128.7, 128.2, 128.0, 127.2, 98.0, 82.0, 22.0, 21.9; IR
d
7.64 (d, J¼8.0 Hz, 2H), 7.31e7.17 (m, 10H),
d
d
(film): 3057, 3036, 2923, 1596, 1492, 1447, 1370, 1174, 1084 cmꢁ1
;
MS (ESI) m/z ([MþH]þ): 594; HRMS (EI) calcd for C29H24INO3S:
593.0522; found: 593.0518.
4.4. General procedure for the synthesis of 6
4.3.10. 3-(4-Fluorophenyl)-4-iodo-5,5-diphenyl-2-tosyl-2,5-
To a solution of propargyl alcohol 1 (0.6 mmol) N-tosyl hy-
droxylamine 2 (0.5 mmol), and NBS (0.6 mmol) in dry DCM (5 mL)
was added Yb(OTf)3 (0.05 mmol) slowly at 25 ꢀC, and the reaction
mixture was stirred at 25 ꢀC for 0.5 h. Saturated aqueous Na2S2O3
was added to quench the reaction and the mixture was extracted
with DCM. The organic layer was washed with brine and dried over
Na2SO4, filtered and concentrated. The residue was purified by flash
column chromatography on silica gel with DCM/hexane as eluent to
give 6.
dihydroisoxazole (4j). White solid (192 mg, 64%), mp 175e176 ꢀC;
1H NMR (500 MHz, CDCl3):
d 7.78e7.70 (m, 2H), 7.33e7.26 (m, 2H),
7.24e7.10 (m, 12H), 6.89 (d, J¼8.0 Hz, 2H), 2.38 (s, 3H); 13C NMR
1
(125 MHz, CDCl3):
d
163.8 (d, JCF¼250 Hz), 145.3, 142.18, 142.16,
132.3 (d, 3JCF¼8 Hz), 129.9, 129.7, 129.6, 128.7, 128.3, 128.0, 126.2 (d,
4JCF¼3 Hz), 115.6 (d, JCF¼22 Hz), 98.2, 82.8, 22.0; IR (film): 3060,
2
1629, 1593, 1507, 1444, 1370, 1170, 1087 cmꢁ1; MS (ESI) m/z
([MþH]þ): 598; HRMS (EI) calcd for C28H21FINO3S: 597.0271;
found: 597.0262.
4.4.1. 4-Bromo-3,5,5-triphenyl-2-tosyl-2,5-dihydroisoxazole
4.3.11. 3-(4-Bromophenyl)-4-iodo-5,5-diphenyl-2-tosyl-2,5-
(6a). White solid (128 mg, 48%); mp 181e182 ꢀC (decomposition);
dihydroisoxazole (4k). White solid (221 mg, 67%); mp 178e179 ꢀC;
1H NMR (500 MHz, CDCl3):
d
7.80e7.73 (m, 2H), 7.52e7.43 (m, 3H),
7.32e7.18 (m, 8H), 7.16e7.08 (m, 4H), 6.89 (d, J¼8.5 Hz, 2H), 2.38 (s,
3H); 13C NMR (125 MHz, CDCl3):
145.2, 141.9, 139.1, 130.4, 130.0,
1H NMR (500 MHz, CDCl3):
d 7.64e7.57 (m, 4H), 7.33e7.17 (m, 8H),
7.16e7.10 (m, 4H), 6.90 (d, J¼8.0 Hz, 2H), 2.38 (s, 3H); 13C NMR
d
(125 MHz, CDCl3):
d
145.3, 142.2, 142.1, 131.72, 131.69, 129.9, 129.7,
129.9, 129.5, 129.3, 129.0, 128.31, 128.27, 128.1, 107.9, 96.9, 22.0; IR
(film): 3057, 1593, 1489, 1441, 1367, 1171, 1084 cmꢁ1; MS (ESI) m/z
([MþNa]þ): 556; HRMS (ESI) calcd for C28H22BrNO3SNa: 556.0393;
found: 556.0374.
129.6, 129.1, 128.7, 128.4, 128.0, 124.8, 98.4, 83.3, 22.0; IR (film):
3060, 3024, 1593, 1483, 1367, 1168, 1087, 1010 cmꢁ1; MS (ESI) m/z
([MþH]þ): 658; HRMS (EI) calcd for C28H21BrINO3S: 656.9470;
found: 656.9474.
4.4.2. 4-Bromo-3,5-diphenyl-5-(p-tolyl)-2-tosyl-2,5-dihydro-iso-
4.3.12. 3-(3-Bromophenyl)-4-iodo-5,5-diphenyl-2-tosyl-2,5-
xazole (6b). White solid (128 mg, 47%); mp 98e100 ꢀC; 1H NMR
(500 MHz, CDCl3): d 7.80e7.73 (m, 2H), 7.50e7.43 (m, 3H),
dihydroisoxazole (4l). White solid (234 mg, 71%); mp 176e177 ꢀC;
1H NMR (500 MHz, CDCl3):
d
7.85 (s, 1H), 7.68 (d, J¼8.0 Hz, 1H), 7.59
7.30e7.18 (m, 5H), 7.14 (d, J¼8.0 Hz, 2H), 7.05e6.95 (m, 4H), 6.89 (d,
(d, J¼8.0 Hz, 1H), 7.40e7.32 (m, 1H), 7.32e7.18 (m, 8H), 7.17e7.10
J¼8.0 Hz, 2H), 2.39 (s, 3H), 2.35 (s, 3H); 13C NMR (125 MHz, CDCl3):
(m, 4H), 6.91 (d, J¼8.0 Hz, 2H), 2.39 (s, 3H); 13C NMR (125 MHz,
d
145.2, 142.0, 139.0, 138.9, 138.1, 130.4, 130.0, 129.9, 129.5, 129.4,
CDCl3):
d
145.4, 142.0, 141.7, 133.4, 133.0, 132.2, 129.9, 129.68,
129.1, 128.7, 128.4, 128.3, 128.2, 128.0, 108.1, 96.9, 22.0, 21.4; IR

10200
Y. Zhu et al. / Tetrahedron 68 (2012) 10194e10200
(film): 3057, 1593, 1492, 1444, 1367, 1171, 1082 cmꢁ1; MS (ESI) m/z
([MþNa]þ): 570; HRMS (ESI) calcd for C29H24BrNO3SNa: 570.0550;
found: 570.0523.
([MþH]þ): 372; HRMS (EI) calcd for C24H21NO3: 371.1521; found:
371.1520.
Acknowledgements
4.4.3. 4-Bromo-5-(4-chlorophenyl)-3,5-diphenyl-2-tosyl-2,5-
dihydroisoxazole (6c). White solid (150 mg, 53%); mp 167e168 ꢀC
We thank the National Nature Science Foundation of China (No.
21032005) for financial support.
(decomposition); 1H NMR (500 MHz, CDCl3):
d 7.80e7.72 (m, 2H),
7.52e7.45 (m, 3H), 7.30e7.20 (m, 5H), 7.17 (d, J¼8.5 Hz, 2H), 7.12
(d, J¼7.5 Hz, 2H), 7.05 (d, J¼8.5 Hz, 2H), 6.93 (d, J¼8.5 Hz, 2H),
Supplementary data
2.42 (s, 3H); 13C NMR (125 MHz, CDCl3):
d 145.6, 141.4, 140.6,
The Supplementary data contains copies of 1H and 13C NMR
spectra along with other experimental details. Supplementary data
related to this article can be found online at http://dx.doi.org/
10.1016/j.tet.2012.09.092.
139.4, 134.4, 130.6, 130.0, 129.9, 129.6, 129.5, 129.4, 128.8, 128.6,
128.4, 128.32, 128.26, 128.2, 107.1, 96.4, 22.0; IR (film): 3060, 1593,
1489, 1444, 1370, 1171, 1087 cmꢁ1; MS (ESI) m/z ([MþNa]þ): 590;
HRMS (ESI) calcd for C28H21BrClNO3SNa: 589.9997; found:
589.9966.
References and notes
4.5. General procedure for the synthesis of 7
1. (a) Giomi, D.; Cordero, F. M.; Machetti, F. In Comprehensive Heterocyclic Chem-
istry III; Alan, R. K., Christopher, A. R., Eric, F. V. S., Richard, J. K. T., Eds.; Elsevier:
Oxford, 2008; p 365; (b) Habeeb, A. G.; Praveen Rao, P. N.; Knaus, E. E. J. Med.
Chem. 2001, 44, 2921; (c) Niho, N.; Kitamura, T.; Takahashi, M.; Mutoh, M.; Sato,
H.; Matsuura, M.; Sugimura, T.; Wakabayashi, K. Cancer Sci. 2006, 97, 1011.
2. Matsumoto, M.; Sakuma, T.; Watanabe, N. Tetrahedron Lett. 2002, 43, 8955.
3. Haino, T.; Tanaka, M.; Ideta, K.; Kubo, K.; Mori, A.; Fukazawa, Y. Tetrahedron Lett.
2004, 45, 2277.
4. For examples on access to isoxazoles, see: (a) Burkhard, J. A.; Tchitchanov, B. H.;
Carreira, E. M. Angew. Chem., Int. Ed. 2011, 50, 5379; (b) Murarka, S.; Studer, A.
Org. Lett. 2011, 13, 2746; (c) Waldo, J. P.; Mehta, S.; Neuenswander, B.; Lush-
ington, G. H.; Larock, R. C. J. Comb. Chem. 2008, 10, 658; (d) Waldo, J. P.; Larock,
R. C. J. Org. Chem. 2007, 72, 9643; (e) Ueda, M.; Sato, A.; Ikeda, Y.; Miyoshi, T.;
Naito, T.; Miyata, O. Org. Lett. 2010, 12, 2594.
5. For examples on access to 2,3-dihydroisoxazoles, see: (a) Yu, X.; Du, B.; Wang,
K.; Zhang, J. Org. Lett. 2010, 12, 1876; (b) Gonzalez-Cruz, D.; Tejedor, D.; Armas,
P.; Morales, E. Q.; Garcia-Tellado, F. Chem. Commun. 2006, 2798; (c) Aschwan-
den, P.; Frantz, D. E.; Carreira, E. M. Org. Lett. 2000, 2, 2331.
6. For examples on access to 4,5-dihydroisoxazoles, see: (a) Zhu, M. K.; Zhao, J. F.;
Loh, T. P. J. Am. Chem. Soc. 2010, 132, 6284; (b) Cecchi, L.; Sarlo, F. D.; Machetti, F.
Chem.dEur. J. 2008, 14, 7903.
7. For examples on access to 2,5-dihydroisoxazoles, see: (a) Knight, D. W.; Proctor,
A. J.; Clough, J. M. Synlett 2010, 628; (b) Yeom, H. S.; Lee, E. S.; Shin, S. Synlett
2007, 2292; (c) Foot, O. F.; Knight, D. W.; Low, A. C. L.; Li, Y. Tetrahedron Lett.
2007, 48, 647; (d) Okitsu, T.; Sato, K.; Potewar, T. M.; Wada, A. J. Org. Chem. 2011,
76, 3438.
8. (a) Zhu, Y. X.; Yin, G. W.; Hong, D.; Lu, P.; Wang, Y. G. Org. Lett. 2011, 13, 1024; (b)
Zhu, Y. X.; Wen, S.; Yin, G. W.; Hong, D.; Lu, P.; Wang, Y. G. Org. Lett. 2011, 13,
3553; (c) Yin, G. W.; Zhu, Y. X.; Zhang, L.; Lu, P.; Wang, Y. G. Org. Lett. 2011, 13,
940.
A
solution of 4 (0.2 mmol), Pd(OAc)2 (0.02 mmol), dppb
(0.02 mmol), i-Pr2NH (0.8 mmol) in DMF (10 mL) and MeOH (1 mL)
was stirred under CO atmosphere (20 atm) at 100 ꢀC for 12 h. When
the reaction was complete, the mixture was filtered and the
methanol was removed under vacuum. The DMF residue was di-
luted with H2O and the mixture was extracted with EtOAc. The
organic layer was dried over Na2SO4, filtered, and evaporated under
vacuum. The residue was purified by flash column chromatography
on silica gel with DCM/hexane as eluent to give 7.
4.5.1. Methyl 3,5,5-triphenyl-4,5-dihydroisoxazole-4-carboxylate
(7a). White solid (42 mg, 58%); mp 181e182 ꢀC; 1H NMR
(500 MHz, CDCl3):
7.42e7.35 (m, 5H), 7.34e7.27 (m, 3H), 7.26e7.21 (m, 1H), 5.13 (s,
1H), 3.21 (s, 3H); 13C NMR (125 MHz, CDCl3):
168.4, 155.2, 143.5,
d 7.72e7.64 (m, 4H), 7.48e7.42 (m, 2H),
d
139.8, 130.6, 129.1, 129.0, 128.8, 128.5, 128.23, 128.16, 127.0, 126.8,
126.3, 95.3, 63.8, 52.6; IR (KBr): 1739, 1617, 1498, 1460, 1314, 1171,
1126 cmꢁ1; MS (ESI) m/z ([MþH]þ): 358; HRMS (EI) calcd for
C23H19NO3: 357.1365; found: 357.1363.
4.5.2. Methyl 3-phenyl-5,5-di-p-tolyl-4,5-dihydroisoxazole-4-
carboxylate (7b). White solid (39 mg, 51%); mp 150e152 ꢀC; 1H
9. CCDC 889064 and 889065 contain the supplementary crystallographic data of
3a and 4a, respectively.
NMR (500 MHz, CDCl3):
d
7.70e7.65 (m, 2H), 7.52 (d, J¼8.5 Hz, 2H),
10. (a) Debleds, O.; Zotto, C. D.; Vrancken, E.; Campagne, J. M.; Retailleau, P. Adv.
Synth. Catal. 2009, 351, 1991; (b) Debleds, O.; Gayon, E.; Ostaszuk, E.; Vrancken,
E.; Campagne, J. M. Chem.dEur. J. 2010, 16, 12207; (c) Gayon, E.; Quinonero, O.;
Lemouzy, S.; Vrancken, E.; Campagne, J. M. Org. Lett. 2011, 13, 6418.
11. For reviews, see: (a) Swaminathan, S.; Narayanan, K. V. Chem. Rev. 1971, 71, 429;
(b) Engel, D. A.; Dudley, G. B. Org. Biomol. Chem. 2009, 7, 4149 For recent ex-
amples, see; (c) Zhu, H. T.; Ji, K. G.; Yang, F.; Wang, L. J.; Zhao, S. C.; Ali, S.; Liu, X.
Y.; Liang, Y. M. Org. Lett. 2011, 13, 684; (d) Hao, L.; Wu, F.; Ding, Z. C.; Xu, S. X.;
Ma, Y. L.; Chen, L.; Zhan, Z. P. Chem.dEur. J. 2012, 18, 6453.
7.40e7.34 (m, 3H), 7.30 (d, J¼8.0 Hz, 2H), 7.17 (d, J¼8.0 Hz, 2H), 7.09
(d, J¼8.0 Hz, 2H), 5.08 (s, 1H), 3.24 (s, 3H), 2.32 (s, 3H), 2.29 (s, 3H);
13C NMR (125 MHz, CDCl3):
d 168.5, 155.2, 140.8, 138.2, 137.8, 136.9,
130.5, 129.4, 129.2, 129.1, 128.9, 126.9, 126.8, 126.1, 95.4, 63.6, 52.6,
21.28, 21.25; IR (film): 1733, 1516, 1447, 1358, 1194, 918 cmꢁ1; MS
(ESI) m/z ([MþH]þ): 386; HRMS (EI) calcd for C25H23NO3: 385.1678;
found: 385.1680.
12. Andres, J.; Cardenas, R.; Silla, E.; Tapia, O. J. Am. Chem. Soc. 1988, 110, 666.
13. Bohm, S.; Exner, O. Org. Biomol. Chem. 2003, 1, 1176.
14. For a review, see: Wei, L. L.; Xiong, H.; Hsung, R. P. Acc. Chem. Res. 2003, 36, 773.
15. For recent examples, see: (a) Khan, A. T.; Ghosh, A.; Khan, M. M. Tetrahedron
Lett. 2012, 53, 2622; (b) Reddy, C. R.; Ramesh, P.; Rao, N. N.; Ali, S. A. Eur. J. Org.
Chem. 2011, 2133; (c) Lin, X. F.; Cui, S. L.; Wang, Y. G. Tetrahedron Lett. 2006, 47,
4509; (d) Jareb, M.; Vrazic, D.; Zupan, M. Tetrahedron 2010, 67, 1355; (e) Nath, J.;
Patel, B. K.; Jamir, L.; Sinha, U. B.; Satyanarayana, K. V. V. V. Green Chem. 2009,
11, 1503.
4.5.3. Methyl 3,5-diphenyl-5-(p-tolyl)-4,5-dihydroisoxazole-4-
carboxylate (7c) mixture of Z and E form. White solid (38 mg,
51%); mp 149e150 ꢀC; 1H NMR (500 MHz, CDCl3):
d 7.72e7.62 (m,
3H), 7.54 (d, J¼8.0 Hz, 1H), 7.43 (d, J¼7.5 Hz, 1H), 7.41e7.35 (m, 4H),
7.33e7.20 (m, 3H), 7.18 (d, J¼8.0 Hz, 1H), 7.10 (d, J¼8.0 Hz, 1H), 5.10
(s, 1H), 3.23 (d, J¼22 Hz, 3H), 2.31 (d, J¼16 Hz, 3H); 13C NMR
€
16. For recent reviews, see: (a) Brennfuhrer, A.; Neumann, H.; Beller, M. Angew.
€
Chem., Int. Ed. 2009, 48, 4114; (b) D’Souza, D. M.; Muller, T. J. J. Chem. Soc. Rev.
(125 MHz, CDCl3):
d 168.5, 155.21, 155.18, 143.7, 140.6, 140.0, 138.3,
2007, 36, 1095.
137.9, 136.8, 130.6, 129.4, 129.1, 129.0, 128.7, 128.2, 126.9, 126.8,
126.20, 126.18, 95.4, 95.3, 63.72, 63.68, 52.63, 52.59, 21.28, 21.26; IR
(KBr): 1617, 1558, 1447, 1314, 1194, 1171 cmꢁ1; MS (ESI) m/z
_
17. Zadrozna, I.; Kurkowska, J.; Kruszewska, H.; Makuch, I. IL Farmaco 2000, 55, 499.
18. Engel, D. A.; Dudley, G. B. Org. Lett. 2006, 8, 4027.
19. Banerjee, R.; King, S. B. Org. Lett. 2009, 11, 4580.