Preparation of isoxazol(in)yl substituted selenides and their further deselenenylation reaction to synthesize 3,5-disubstituted isoxazoles

Article abstract of DOI:10.1016/j.tet.2004.10.071

We report a mild 1,3-dipolar cycloaddition protocol for the preparation of 3-aryl-5-phenylselenomethyl isoxazoles and isoxazolines regioselectively. The former was further reacted with LDA and electrophilic substrates followed by selenoxide syn-eliminatio

Full text of DOI:10.1016/j.tet.2004.10.071

Tetrahedron 61 (2005) 501–506
Preparation of isoxazol(in)yl substituted selenides and
their further deselenenylation reaction to synthesize
3,5-disubstituted isoxazoles
Wei Ming Xu,a,b E. Tanga and Xian Huanga,c,
*
aDepartment of Chemistry, Zhejiang University (Campus Xixi), Hangzhou 310028, People’s Republic of China
bCenter of Analysis and Measurement, Zhejiang University, Hangzhou 310028, People’s Republic of China
cLaboratory of Organometallic Chemistry, Chinese Academy of Sciences Shanghai 200032, People’s Republic of China
Received 7 May 2004; revised 6 October 2004; accepted 12 October 2004
Available online 11 November 2004
Abstract—We report a mild 1,3-dipolar cycloaddition protocol for the preparation of 3-aryl-5-phenylselenomethyl isoxazoles and
isoxazolines regioselectively. The former was further reacted with LDA and electrophilic substrates followed by selenoxide syn-elimination
to afford 3-aryl-5-E-substituted-ethenyl isoxazoles stereoselectively and the latter was subjected to a ‘two-step’ elimination to afford 3-aryl-
5-methyl isoxazoles.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
and 3-aryl-5-E-substituted ethenyl isoxazoles 5, which
cannot be obtained via the reaction of Wittig reagents
with the corresponding aldehydes when the unstable Wittig
reagents are used.7
1,3-Dipolar cycloaddition reactions are of the most
important synthetic manipulations allowing the construction
of five-membered carbocycles and heterocycles.1 Among
them, nitrile oxides have been shown to be effective 1,3-
dipoles and they undergo smooth reactions with substituted
alkynes or alkenes to give substituted isoxazoles or
isoxazolines, respectively. Both classes of heterocycles are
versatile intermediates for the synthesis of complex natural
products and biologically active compounds2 that are
observed in many therapeutic agents.
2. Results and discussion
We began our experiment from diphenyl diselenide, which
was treated with NaBH4 and propargyl bromide (or allyl
bromide) to get phenylpropargyl selenide 2a (or phenylallyl
selenide 2b).8 Without any further purification, phenyl-
propargyl selenide was then reacted with hydroximoyl
halide and Et3N. In this process Et3N was slowly added
dropwise in 6 h in order to avoid the dimerization of the
nitrile oxides. 3-Aryl-5-phenylselenomethyl isoxazoles 3a
were obtained in moderate to good yields. The use of
phenylallyl selenide in place of phenylpropargyl selenide
gave 3-aryl-5-phenylselenomethyl isoxazolines 3b using the
same procedure (Scheme 1). The results are summarized in
Table 1.
Diorganic selenides have attracted considerable interest
because of their potential as anticancer and antioxidant
agents.3 They are also key intermediates4 for they can be
efficiently introduced, manipulated, and removed under
mild conditions and usually in good yields. But to date,
there are very rare reports on the 1,3-dipolar cycloaddition
of phenylseleno-substituted alkynes and alkenes.5 Our
research group6 has been interested in the application of
selenium in organic synthesis for several years. Here we
reported a mild, regioselective protocol to prepare 3-aryl-5-
phenylselenomethyl isoxazoles and isoxazolines 3 and their
further applications to prepare 3-aryl-5-methyl isoxazoles 7
A useful feature of organoselenium is its ability to stabilize
adjacent carbanions. Although the direct deprotonation of
phenylselenomethyl isoxazolines 3b (aryl alkyl selenide) is
difficult,9 the co-stabilization of isoxazolyl- and phenylse-
leno- made phenylselenomethyl isoxazoles 3a react with
LDA smoothly to form a-seleno alkyllithium (Scheme 2,
step 1). Because of its easy availability and high
nucleophilicity, a-seleno alkyllithium plays an important
Keywords: 1,3-Dipolar cycloaddition; Isoxazoles; Isoxazolines; Selenoxide
syn-elimination.
* Corresponding author. Fax: C86 571 88807077;
e-mail: huangx@mail.hz.zj.cn
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.10.071

502
W. M. Xu et al. / Tetrahedron 61 (2005) 501–506
Scheme 1. Reagents and conditions: (a) NaBH4, THF, EtOH, rt, 1 h; (b) propargyl bromide(allyl bromide), THF, rt, 2 h; (c) R1C(Cl)]NOH, CH2Cl2, Et3N, rt,
6 h.
Although a b-H exists in the molecule, 3-aryl-5-phenyl-
selenomethyl isoxazolines 3b did not undergo selenoxide
syn-elimination even we mixed them with H2O2 in THF and
stirred at 50 8C for 1 h (Scheme 3, step c). To solve this
Table 1. Synthesis of 3-aryl-5-phenylselenomethyl isoxazoles and
isoxazolines
Producta
R1
Yield (%)b
3aa
3ab
3ac
3ad
3ae
3ba
3bb
3bc
3bd
3be
4-BrC6H4
4-CH3C6H4
4-ClC6H4
4-FC6H4
79
78
76
67
78
86
83
84
56
73
C6H5
4-CH3OC6H4
4-BrC6H4
4-CH3C6H4
4-NO2C6H4
4-FC6H4
a All the products were characterized by IR, H NMR, 13C NMR and MS
spectroscopy.
1
Scheme 3. Reagents and conditions: (a) CH3I, NaI, DMF, 80 8C, 20 h; (b)
DBU or NaCN, THF, reflux, 12 h; (c) H2O2, THF, 50 8C, 1 h.
b Isolated yield.
Scheme 2. Reagents and conditions: (a) LDA (1.0 equiv), THF, K78 8C, 1.5 h; (b) R2CH2X (1.0 equiv), THF, K78 to K50 8C, 1 h; (c) H2O2, THF, 0 8C, 1 h,
then rt, 20 min.
role in organic synthesis, which allows the formation of new
functionalized carbon–carbon bonds when it is used to react
with carbon electrophiles. Alkyl halides are used here as
carbon electrophiles to perform the a-alkylation reaction to
afford alkylated product 4, which followed by selenoxide
syn-elimination to obtain 3-aryl-5-E-substituted ethenyl
isoxazoles 5 stereoselectively (Scheme 2). The results are
summarized in Table 2.
problem, we used a mild ‘two-step’ deselenium protocol in
which 3-aryl-5-phenylselenomethyl isoxazolines first
reacted with NaI and CH3I in DMF to afford 3-aryl-5-
iodomethyl isoxazoline,10 which was then treated with DBU
to afford 3-aryl-5-methyl isoxazoles almost quantitatively
(Scheme 3). It should be pointed out that NaCN could take
the place of DBU as a base to perform the reaction. The
results are summarized in Table 3.
Table 3. Synthesis of 3-aryl-5-methyl isoxazoles
Product
R1
Yield (%)a
Table 2. Synthesis of 3-aryl-5-E-substituted-ethenyl isoxazoles
Producta
R1
R2
Yield (%)b
7a
7b
7c
4-CH3OC6H4
4-FC6H4
4-CH3C6H4
4-NO2C6H4
C6H5
82
79
86
87
83
85
5a
5b
5c
5d
4-CH3OC6H4
4-CH3C6H4
4-ClC6H4
CH2]CH
CH3
CH2]CH
82
78
76
80
7d
7e
7eb
C6H5
4-CH3C6H4
a Isolated yield.
5e
5f
5g
5h
5i
4-CH3C6H4
4-CH3C6H4
4-FC6H4
4-BrC6H4
4-CH3C6H4
C6H5
83
77
74
71
76
b NaCN was used otherwise DBU was used as a base.
CH3OOC
CH2]C(CH3)
CH3
CH2]CH
3. Conclusion
a All the products were characterized by IR, H NMR, 13C NMR and MS
spectroscopy.
1
We have developed a mild 1,3-dipolar cycloaddition
protocol to prepare 3-aryl-5-phenylselenomethyl isoxazoles
b Isolated yield.

W. M. Xu et al. / Tetrahedron 61 (2005) 501–506
503
and isoxazolines regioselectively. The former was further
reacted with LDA and electrophilic substrates followed by
selenoxide syn-elimination to afford 3-aryl-5-E-substituted-
ethenyl isoxazoles, and the synthesis was general with
excellent control of E geometry.7 The latter underwent a
‘two-step’ elimination to afford 3-aryl-5-methyl isoxazoles.
C16H12ClNOSe: C, 55.11; H, 3.47; N, 4.02. Found: C,
55.24; H, 3.37; N, 4.11.
4.1.4. Compound 3ad. 3-(4-Fluoro-phenyl)-5-phenyl-
selenomethyl isoxazole; pale yellow solid, mp 59–60 8C;
1H NMR (CDCl3) d 7.75–7.72 (2H, m), 7.57–7.55 (2H, m),
7.33–7.31 (3H, m), 7.14 (2H, t, JZ8.8 Hz), 6.21 (1H, s),
4.13 (2H, s); 13C NMR (CDCl3) d 171.2, 164.2 (JZ
248.6 Hz), 162.0, 134.6, 129.7, 129.2, 129.0 (JZ8.3 Hz),
128.6, 125.6 (JZ3.3 Hz), 116.4 (JZ21.9 Hz), 100.6, 20.7;
MS m/z 176 (100), 333 (MCC1); IR nmax (cmK1) 3113,
3024, 1607, 1591, 1435, 735, 690. Elemental analysis calcd
for C16H12FNOSe: C, 57.84; H, 3.64; N, 4.22. Found: C,
57.98; H, 3.71; N, 4.10.
4. Experimental
1
The melting points were uncorrected. H NMR (400 MHz)
and 13C NMR (100 MHz) spectra were recorded on a Bruker
Avance 400 spectrometer in CDCl3 with TMS as the
internal standard; chemical shifts were quoted in ppm and J
values were given in Hz. IR spectra recorded on a IR-408
spectrometer. EIMS was run on a HP 5989B mass
spectrometer. Elemental analysis was run on Thermo-
finnigan Flash EA 1112.
4.1.5. Compound 3ae. 3-Phenyl-5-phenylselenomethyl
isoxazole; pale yellow solid, mp 54–56 8C; 1H NMR
(CDCl3) d 7.74–7.72 (2H, m), 7.55–7.53 (2H, m), 7.44–
7.42 (3H, m), 7.30–7.28 (3H, m), 6.23 (1H, s), 4.12 (2H, s);
13C NMR (CDCl3) d 170.9, 162.9, 134.6, 130.4, 129.7,
129.5, 129.3, 128.6, 127.2, 100.8. 20.8; MS m/z 77 (100),
315 (MCC1); IR nmax (cmK1) 3119, 3050, 1600, 1577,
1469, 1439, 768, 691. Elemental analysis calcd for
C16H13NOSe: C, 61.15; H, 4.17; N, 4.46. Found: C,
61.30; H, 4.09; N, 4.34.
4.1. General procedure of 3-aryl-5-phenylselenomethyl
isoxazoles 3a and isoxazolines 3b
Phenylpropargyl selenide (or phenylallyl selenide)
(1 mmol) was added to a mixture of hydroximoyl chloride
(1.1 mmol) in 10 mL CH2Cl2 (prepared from 1.1 mmol of
aldoxime and 1.1 mmol of NCS stirring at rt for about 3 h
before use). A mixture of Et3N (1.2 mmol) in 10 mL
CH2Cl2 was slowly dropwised in 6 h. After the reaction, the
mixture was washed with 15 mL saturated NaHCO3 aq
solution and 15 mL water then dried over MgSO4. Dryness
followed by purification via flash chromatography with
n-hexanes–EtOAc (9:1, v/v) as the eluent to give 3a (or 3b).
4.1.6. Compound 3ba. 3-(4-Methoxyl-phenyl)-5-phenyl-
selenomethyl isoxazoline; pale yellow solid, mp 75–76 8C;
1H NMR (CDCl3) d 7.64–7.56 (4H, m), 7.31–7.28 (3H, m),
6.92 (2H, d, JZ8.8 Hz), 4.89–4.87 (1H, m), 3.44 (1H, dd,
J1Z10.0 Hz, J2Z16.8 Hz), 3.85 (3H, s), 3.34 (1H, dd, J1Z
4.4 Hz, J2Z12.0 Hz), 3.19 (1H, dd, J1Z6.8 Hz, J2Z
16.8 Hz), 3.03 (1H, dd, J1Z9.2 Hz, J2Z12.8 Hz); 13C
NMR (CDCl3) d 161.5, 156.2, 133.6, 129.7, 129.2, 128.7,
127.9, 122.4, 114.5, 80.5, 55.7, 40.7, 31.8; MS m/z 176
(100), 346 (MCC1); IR nmax (cmK1) 2960, 1609, 1517,
1253, 835, 728, 689. Elemental analysis calcd for
C17H17NO2Se: C, 58.96; H, 4.95; N, 4.04. Found: C,
59.10; H, 4.89; N, 4.14.
4.1.1. Compound 3aa. 3-(4-Bromo-phenyl)-5-phenyl-
selenomethyl isoxazole; pale yellow solid; mp 81–82 8C;
1H NMR (CDCl3) d 7.61–7.54 (6H, m), 7.32–7.30 (3H, m),
6.21 (1H, s), 4.13 (2H, s); 13C NMR (CDCl3) d 171.3, 162.0,
134.6, 132.5, 129.7, 129.2, 128.7, 128.6, 128.4, 124.7,
100.6, 20.7; MS m/z 157 (100), 393 (MC); IR nmax (cmK1
)
3442, 3113, 1632, 1430, 1074, 733. Elemental analysis
calcd for C16H12BrNOSe: C, 48.88; H, 3.08; N, 3.56. Found:
C, 48.99; H, 2.96; N, 3.47.
4.1.7. Compound 3bb. 3-(4-Bromo-phenyl)-5-phenyl-
selenomethyl isoxazoline; pale yellow solid, mp 101–
1
103 8C; H NMR (CDCl3) d 7.59–7.50 (6H, m), 7.32–7.28
(3H, m), 4.95–4.92 (1H, m), 3.43 (1H, dd, J1Z10.4 Hz,
J2Z16.8 Hz), 3.34 (1H, dd, J1Z4.4 Hz, J2Z12.4 Hz), 3.18
(1H, dd, J1Z6.8 Hz, J2Z16.8 Hz), 3.02 (1H, dd, J1Z
9.2 Hz, J2Z12.8 Hz); 13C NMR (CDCl3) d 155.8, 133.7,
132.3, 129.7, 129.0, 128.8, 128.5, 128.0, 124.8, 81.1, 40.2,
31.7; MS m/z 91 (100), 395 (MCC2); IR nmax (cmK1) 1634,
1589, 1436, 1118, 823, 734, 690. Elemental analysis calcd
for C16H14BrNOSe: C, 48.63; H, 3.57; N, 3.54. Found: C,
48.52; H, 3.66; N, 3.63.
4.1.2. Compound 3ab. 3-(4-Methyl-phenyl)-5-phenyl-
selenomethyl isoxazole; pale yellow solid, mp 40–41 8C;
1H NMR (CDCl3) d 7.64 (2H, d, JZ7.6 Hz), 7.56 (2H, d,
JZ7.6 Hz), 7.31–7.25 (5H, m), 6.22 (1H, s), 4.13 (2H, s),
2.41 (3H, s); 13C NMR (CDCl3) d 170.7, 162.8, 140.5,
134.6, 129.9, 129.7, 129.3, 128.6, 127.0, 126.6, 100.7, 21.8,
20.8; MS m/z 172 (100), 329 (MCC1); IR nmax (cmK1
)
3441, 3127, 1615, 1600, 1431, 739, 671. Elemental analysis
calcd for C17H15NOSe: C, 62.20; H, 4.61; N, 4.27. Found:
C, 62.08; H, 4.71; N, 4.15.
4.1.8. Compound 3bc. 3-(4-Methyl-phenyl)-5-phenyl-
selenomethyl isoxazoline; pale yellow solid, mp 59–60 8C;
1H NMR (CDCl3) d 7.59–7.54 (4H, m), 7.31–7.28 (3H, m),
7.22 (2H, d, JZ7.2 Hz), 4.92–4.89 (1H, m), 3.43 (1H, dd,
J1Z10.0 Hz, J2Z16.8 Hz), 3.32 (1H, dd, J1Z4.4 Hz, J2Z
12.0 Hz), 3.19 (1H, dd, J1Z6.8 Hz, J2Z16.8 Hz), 3.02 (1H,
dd, J1Z9.2 Hz, J2Z12.8 Hz), 2.40 (3H, s); 13C NMR
(CDCl3) d 156.6, 140.7, 133.6, 129.8, 129.7, 129.2, 127.9,
127.1, 127.0, 80.6, 40.6, 31.9, 21.8; MS m/z 91 (100), 330
(MC); IR nmax (cmK1) 2924, 2854, 1579, 1436, 1376, 895,
4.1.3. Compound 3ac. 3-(4-Chloro-phenyl)-5-phenyl-
selenomethyl isoxazole; pale yellow solid, mp 70–71 8C;
1H NMR (CDCl3) d 7.68 (2H, d, JZ8.4 Hz), 7.56–7.54 (2H,
m),7.42 (2H, d, JZ8.4 Hz), 7.32–7.28 (3H, m), 6.21 (1H, s),
4.13 (2H, s); 13C NMR (CDCl3) d 171.3, 161.9, 136.4,
134.6, 129.7, 129.5, 129.2, 128.6, 128.4, 127.9, 100.6, 20.7;
MS m/z 192 (100), 348 (MCC1); IR nmax (cmK1) 3112,
3054, 1633, 1602, 1430, 736. Elemental analysis calcd for

504
W. M. Xu et al. / Tetrahedron 61 (2005) 501–506
817, 727, 688. Elemental analysis calcd for C17H17NOSe:
C, 61.82; H, 5.19; N, 4.24. Found: C, 61.96; H, 5.11; N,
4.17.
8.4 Hz), 6.64–6.56 (1H, m), 6.41 (1H, d, JZ16.0 Hz), 6.36
(1H, s), 2.42 (3H, s), 1.97 (3H, d, JZ7.2 Hz); 13C NMR
(CDCl3) d 169.3, 162.9, 140.3, 134.0, 129.9, 127.0, 126.8,
117.6, 98.1, 21.8, 19.0; MS m/z 69 (100), 199 (MC); IR nmax
(cmK1) 1666, 1563, 1525, 1427, 965, 819, 788. Elemental
analysis calcd for C13H13NO: C, 78.36; H, 6.58; N, 7.03.
Found: C, 78.30; H, 6.49; N, 6.95.
4.1.9. Compound 3bd. 3-(4-Nitro-phenyl)-5-phenylseleno-
methyl isoxazoline; pale yellow solid, mp 95–96 8C; H
1
NMR (CDCl3) d 8.25 (2H, d, JZ7.2 Hz), 7.79 (2H, d, JZ
7.2 Hz), 7.60–7.56 (2H, m), 7.33–7.28 (3H, m), 5.04–4.99
(1H, m), 3.47 (1H, dd, J1Z10.4 Hz, J2Z16.8 Hz), 3.34 (1H,
dd, J1Z4.4 Hz, J2Z12.4 Hz), 3.23 (1H, dd, J1Z6.8 Hz,
J2Z16.8 Hz), 3.04 (1H, dd, J1Z9.2 Hz, J2Z12.8 Hz); 13C
NMR (CDCl3) d 155.1, 148.9, 135.9, 133.7, 129.8, 128.9,
128.1, 127.8, 124.4, 81.9, 39.8, 31.6; MS m/z 91 (100), 362
(MCC1); IR nmax (cmK1) 1634, 1589, 1436, 1118, 823,
734, 690. Elemental analysis calcd for C16H14N2O3Se: C,
53.20; H, 3.91; N, 7.75. Found: C, 53.04; H, 3.80; N, 7.64.
4.2.3. Compound 5c. 3-(4-Chloro-phenyl)-5-(E-1,3-but-
dienyl) isoxazole; pale yellow solid, mp 75–76 8C; 1H
NMR (CDCl3) d 7.76 (2H, d, JZ8.0 Hz), 7.45 (2H, d, JZ
8.0 Hz), 7.03 (1H, dd, J1Z7.2 Hz, J2Z16.0 Hz), 6.53–6.47
(3H, m), 5.55 (1H, d, JZ8.8 Hz), 5.42 (1H, d, JZ8.8 Hz);
13C NMR (CDCl3) d 169.4, 162.1, 136.4, 136.2, 136.1,
129.6, 128.4, 128.0, 122.8, 117.1, 99.6; MS m/z 66 (100),
231 (MC); IR nmax (cmK1) 3403, 3025, 1627, 1424, 965,
819, 692. Elemental analysis calcd for C13H10ClNO: C,
67.40; H, 4.35; N, 6.05. Found: C, 67.50; H, 4.28; N, 5.98.
4.1.10. Compound 3be. 3-(4-Fluoro-phenyl)-5-phenyl-
selenomethyl isoxazoline; pale yellow solid, mp 83–84 8C;
1H NMR (CDCl3) d 7.66–7.61 (2H, m), 7.60–7.57 (2H, m),
7.32–7.28 (3H, m), 7.08 (2H, t, JZ8.8 Hz), 5.95–4.90 (1H,
m), 3.43 (1H, dd, J1Z10.4 Hz, J2Z16.8 Hz), 3.32 (1H, dd,
J1Z4.4 Hz, J2Z12.8 Hz), 3.19 (1H, dd, J1Z6.8 Hz, J2Z
16.8 Hz), 3.02 (1H, dd, J1Z9.2 Hz, J2Z12.8 Hz); 13C
NMR (CDCl3) d 164.2 (JZ248.6 Hz), 155.6, 133.6, 129.7,
129.1, 129.0 (JZ8.3 Hz), 128.0, 126.1 (JZ3.0 Hz), 116.2
(JZ21.4 Hz), 80.9, 40.5, 31.8; MS m/z 164 (100), 335
(MCC1); IR nmax (cmK1) 3071, 1601, 1512, 1228, 834,
733, 690. Elemental analysis calcd for C16H14FNOSe: C,
57.49; H, 4.22; N, 4.19. Found: C, 57.42; H, 4.15; N, 4.28.
4.2.4. Compound 5d. 3-(4-Methyl-phenyl)-5-(epoxy-E-
ethenyl) isoxazole; pale yellow solid, mp 70–72 8C; 1H
NMR (CDCl3) d 7.71 (2H, d, JZ7.6 Hz), 7.28 (2H, d, JZ
7.6 Hz), 6.74 (1H, d, JZ16.0 Hz), 6.49 (1H, s), 6.31 (1H,
dd, J1Z7.6 Hz, J2Z16.4 Hz), 3.56–3.54 (1H, m), 3.13–3.10
(1H, m), 2.81–2.79 (1H, m), 2.42 (3H, s); 13C NMR (CDCl3)
d 167.7, 163.0, 140.6, 134.3, 130.0, 127.0, 126.4, 119.0,
100.2, 51.8, 49.9, 21.8; MS m/z 158 (100), 227 (MC); IR
nmax (cmK1) 1608, 1515, 1414, 895, 817, 727, 670.
Elemental analysis calcd for C14H13NO2: C, 73.99; H,
5.77; N, 6.16. Found: C, 73.87; H, 5.87; N, 6.08.
4.2. General procedure of 3-aryl-5-substituted ethenyl
isoxazoles 5
4.2.5. Compound 5e. 3-(4-Methyl-phenyl)-5-(E-phenyl-
ethenyl) isoxazole; pale yellow solid, mp 98–99 8C; 1H
NMR (CDCl3) d 7.73 (2H, d, JZ7.6 Hz), 7.54–7.52 (2H,
m), 7.42–7.34 (4H, m), 7.27 (2H, d, JZ7.6 Hz), 6.99 (1H, d,
JZ16.4 Hz), 6.54 (1H, s), 2.41 (3H, s); 13C NMR (CDCl3) d
169.2, 163.1, 140.5, 136.0, 135.2, 130.0, 129.5, 129.3,
127.5, 127.1, 126.7, 113.6, 99.8, 21.8; MS m/z 261 (MC,
100); IR nmax (cmK1) 1642, 1582, 1426, 993, 829, 747, 697.
Elemental analysis calcd for C18H15NO: C, 82.73; H, 5.79;
N, 5.36. Found: C, 82.66; H, 5.88; N, 5.44.
3-Aryl-5-phenylselenomethyl isoxazole 3a (0.5 mmol) was
solved in 10 mL dry THF, cooled to K78 8C, and added
dropwise LDA (2 M in THF/hexane, 0.3 mL) under
nitrogen. After stirring at K78 8C for 0.5 h, a solution of
alkyl halide (0.6 mmol) in 1 mL of dry THF was added. The
suspension was stirred at K78 8C for another 0.5 h. Slowly
warm up to K50 8C in 0.5 h then quenched with 0.1 mL
H2O. To the mixture was added 30% (aq) H2O2 (0.5 mL)
and stirred at 0 8C for 1 h followed by 20 min at room
temperature. After the reaction, 20 mL CH2Cl2 was added.
The mixture was washed with 15 mL saturated NaHCO3 aq
solution and 15 mL water and dried over MgSO4. Dryness
followed by purification via flash chromatography with
n-hexanes–EtOAc (9:1, v/v) as the eluent to give 5.
4.2.6. Compound 5f. 3-(4-Methyl-phenyl)-5-(methoxy-
carbonyl-E-ethenyl) isoxazole; pale yellow solid, mp 143–
1
145 8C; H NMR (CDCl3) d 7.72 (2H, d, JZ7.6 Hz), 7.55
(1H, d, JZ16.0 Hz), 7.30 (2H, d, JZ7.6 Hz), 6.76 (1H, s),
6.68 (1H, d, JZ16.0 Hz), 3.86 (3H, s), 2.43 (3H, s); 13C
NMR (CDCl3) d 166.6, 166.3, 163.3, 141.0, 130.1, 128.1,
127.1, 125.9, 123.7, 104.5, 52.5, 21.8; MS m/z 158 (100),
243 (MC); IR nmax (cmK1) 1711, 1651, 1560, 1528, 1429,
1385, 1312, 1262, 1173, 972, 816. Elemental analysis calcd
for C14H13NO3: C, 69.12; H, 5.39; N, 5.76. Found: C, 68.98;
H, 5.52; N, 5.89.
4.2.1. Compound 5a. 3-(4-Methoxyl-phenyl)-5-(E-1,3-
butdienyl) isoxazole; pale yellow solid, mp 47–49 8C; H
1
NMR (CDCl3) d 7.76 (2H, d, JZ8.2 Hz), 7.04–6.97 (3H,
m), 6.52–6.45 (3H, m), 5.53 (1H, d, JZ16.8 Hz), 5.41 (1H,
d, JZ10.4 Hz), 3.87 (3H, s); 13C NMR (CDCl3) d 168.8,
162.6, 161.4, 136.2, 135.7, 128.5, 122.4, 122.0, 117.4,
4.2.7. Compound 5g. 3-(4-Fluoro-phenyl)-5-(2-methyl-E-
1,3-butdienyl) isoxazole; yellow low pointing solid; 1H
NMR (CDCl3) d 7.82–7.79 (2H, m), 7.18–7.10 (3H, m),
6.48 (1H, s), 6.44 (1H, d, JZ16.4 Hz), 5.30 (2H, d, JZ
12.4 Hz), 1.97 (3H, s); 13C NMR (CDCl3) d 169.3, 163.8
(JZ248.6 Hz), 161.7, 140.9, 137.9, 128.6 (JZ8.1 Hz),
125.3 (JZ4.3 Hz), 121.6, 116.0 (JZ21.7 Hz), 113.3, 98.9,
18.0; MS m/z 229 (100, MC); IR nmax (cmK1) 3062, 3028,
1624, 1435, 975, 735, 692. Elemental analysis calcd for
114.7, 99.7, 56.7; MS m/z 227 (MC, 100); IR nmax (cmK1
)
3405, 3027, 1623, 1495, 1449, 967, 759, 690. Elemental
analysis calcd for C14H13NO2: C, 73.99; H, 5.77; N, 6.16.
Found: C, 74.10; H, 5.66; N, 6.10.
4.2.2. Compound 5b. 3-(4-Methyl-phenyl)-5-(1-E-pro-
penyl) isoxazole; pale yellow solid, mp 74–76 8C; 1H
NMR (CDCl3) d 7.71 (2H, d, JZ8.4 Hz), 7.27 (2H, d, JZ

W. M. Xu et al. / Tetrahedron 61 (2005) 501–506
505
C14H12FNO: C, 73.35; H, 5.28; N, 6.11. Found: C, 73.22; H,
5.39; N, 6.01.
140.0, 129.5, 126.6, 126.5, 99.6, 21.3, 12.3; MS m/z 173
(100, MC); IR nmax (cmK1) 3058, 1622, 1599, 1378, 1222,
829. Elemental analysis calcd for C11H11NO: C, 76.28; H,
6.40; N, 8.09. Found: C, 76.39; H, 6.49; N, 7.97.
4.2.8. Compound 5h. 3-(4-Bromo-phenyl)-5-(1-E-pro-
penyl) isoxazole; pale yellow solid, mp 76–78 8C; 1H
NMR (CDCl3) d 7.69 (2H, d, JZ6.8 Hz), 7.30 (2H, d, JZ
6.8 Hz), 6.65–6.59 (1H, m), 6.38 (1H, d, JZ16.0 Hz), 6.36
(1H, s), 1.97 (3H, d, JZ7.2 Hz); 13C NMR (CDCl3) d 169.8,
162.0, 134.5, 132.5, 128.7, 128.6, 124.5, 117.4, 97.9, 19.1;
MS m/z 69 (100), 264 (97, MC), 266 (94, MCC2); IR nmax
(cmK1) 1666, 1593, 1559, 1501, 1424, 1376, 961, 846, 813,
774, 505. Elemental analysis calcd for C12H10BrNO: C,
54.57; H, 3.82; N, 5.30. Found: C, 54.70; H, 3.70; N, 5.42.
4.3.4. Compound 7d. 3-(4-Nitro-phenyl)-5-methyl isoxa-
1
zole; white solid; mp 153–155 8C (lit.11 154–155 8C); H
NMR (CDCl3) d 8.22 (2H, d, JZ7.6 Hz), 7.80 (2H, d, JZ
7.6 Hz), 6.55 (1H, s), 2.61 (3H, s).
4.3.5. Compound 7e. 3-Phenyl-5-methyl isoxazole; white
1
solid; mp 40–42 8C (lit.11 41–42 8C); H NMR (CDCl3) d
7.79–7.77 (2H, m), 7.45–7.43 (3H, m), 6.29 (1H, s), 2.48
(3H, s).
4.2.9. Compound 5I. 3-(4-Methyl-phenyl)-5-(E-1,3-but-
dienyl) isoxazole; yellow low pointing solid; 1H NMR
(CDCl3) d 7.72 (2H, d, JZ8.2 Hz), 7.28 (2H, d, JZ8.2 Hz),
7.02 (1H, dd, J1Z10.4 Hz, J2Z15.6 Hz), 6.53–6.47 (3H,
m), 5.53 (1H, d, JZ16.8 Hz), 5.17 (1H, d, JZ10.4 Hz), 2.43
(3H, s); 13C NMR (CDCl3) d 168.9, 163.0, 140.5, 136.2,
135.8, 130.0, 127.1, 126.6, 122.4, 117.4, 99.9, 21.8; MS m/z
158 (100), 211 (MC); IR nmax (cmK1) 3405, 3027, 1624,
1493, 1449, 967, 753, 692. Elemental analysis calcd for
C14H13NO: C, 79.59; H, 6.20; N, 6.63. Found: C, 79.38; H,
6.29; N, 6.72.
Acknowledgements
We are grateful to the Natural Science Foundation of China
(Project No.20332060) and the CAS Academician
Foundation of Zhejiang Province.
References and notes
4.3. General procedure of 3-aryl-5-methyl isoxazoles 7
1. For reviews, see the following. (a) Padwa, A. 1,3-Dipolar
Cycloaddition Chemistry; Wiley: New York, 1984. (b) Torsell,
K. G. B. Nitrile Oxides, Nitrones and Nitronates in Organic
Synthesis; VCH: New York, 1988. (c) Padwa, A.; Pearson,
W. H. The Chemistry of Heterocyclic Compounds, Volume 59:
Synthetic Applications of 1,3-Dipolar Cycloaddition
Chemistry Toward Heterocycles and Natural Products;
Wiley: New York, 2002.
3-Aryl-5-phenylselenomethyl isoxazoline 3b (0.5 mmol),
NaI (0.5 g), CH3I (0.5 mL) and 5 mL DMF were mixed
together and the mixture was stirred at 80 8C for 20 h. After
the reaction, 20 mL CH2Cl2 was added. The mixture was
washed with 15 mL saturated NaHCO3 aq solution and
water (15 mL!2) and dried over MgSO4. Dryness followed
by purification via flash chromatography with n-hexanes–
EtOAc (9:1, v/v) as the eluent to give 6. The obtained 6 was
dissolved in 5 mL DMF–THF (2:3, v/v), to the mixture
DBU (0.8 mmol) was added. The mixture was stirred at
90 8C for 10 h. After the reaction, 20 mL CH2Cl2 was
added. The mixture was washed with 20 mL saturated
NaHCO3 aq solution and water (15 mL!3) and dried over
MgSO4. Dryness without further purification gave 7 as
single products.
2. (a) Talley, J.; Brown, D. L.; Carter, J. S.; Graneto, M. J.;
Koboldt, C. M.; Masferrer, L.; Perkins, W. E.; Rogers, S.;
Shaffer, A. F.; Zhang, Y.; Zweifel, B. S.; Seibert, K. J. Med.
Chem. 2000, 43, 775–777. (b) Simoni, D.; Roberti, M.;
Invidiata, F. P.; Rondanin, R.; Baruchello, R.; Malagutti, C.;
Mazzali, A.; Rossi, M.; Grimaudo, S.; Capone, F.; Dusonchet,
L.; Meli, M.; Raimondi, M. V.; Landino, M.; D’Allesandro,
N.; Tolomeo, M.; Arindam, D.; Lu, S.; Benbrook, D. M.
J. Med. Chem. 2001, 44, 2308–2318. (c) Koiowski, A. P. Acc.
Chem. Res. 1984, 17, 410–416.
4.3.1. Compound 7a. 3-(4-Methoxyl-phenyl)-5-methyl
1
isoxazole; white solid; mp 92–93 8C (lit.11 92–93 8C); H
3. (a) El-Bayoumy, K. Nutr. Cancer 2001, 40, 4–5. (b) Back,
T. G.; Moussa, Z. J. Am. Chem. Soc. 2003, 125, 13455–13460.
(c) Back, T. G.; Moussa, Z.; Parvez, M. Angew. Chem., Int. Ed.
2004, 43, 1268–1270.
NMR (CDCl3) d 7.72 (2H, d, JZ8.4 Hz), 6.96 (2H, d, JZ
8.4 Hz), 6.24 (1H, s), 3.85 (3H, s), 2.46 (3H, s).
4.3.2. Compound 7b. 3-(4-Fluoro-phenyl)-5-methyl iso-
xazole; white solid, mp 48–50 8C; 1H NMR (CDCl3) d 7.79–
7.75 (2H, m), 7.14 (2H, d, JZ8.4 Hz), 6.26 (1H, s), 2.48
(3H, s); 13C NMR (CDCl3) d 170.1, 163.7 (JZ249.1 Hz),
161.6, 126.6 (JZ8.2 Hz), 125.5 (JZ3.8 Hz), 115.9 (JZ
4. (a) Krief, A. Comprehensive Organic Chemistry; Pergamon:
Oxford, 1991. (b) Liotta, D. Organoselenium Chemistry;
Wiley: New York, 1987. (c) Wirth, T. Organoselenium
Chemistry; Springer: Berlin, 2000. (d) Back, T. G. Organo-
selenium Chemistry; Oxford University Press: Oxford, 1999.
5. Sheng, S. R.; Liu, X. L.; Xu, Q.; Song, C. S. Synthesis 2003,
2763–2764.
21.6 Hz), 99.6, 12.4; MS m/z 177 (MC, 100); IR nmax (cmK1
)
3139, 1614, 1596, 1525, 1432, 1226, 844, 795. Elemental
analysis calcd for C10H8FNO: C, 67.79; H, 4.55; N, 7.91.
Found: C, 67.88; H, 3.46; N, 7.79.
6. (a) Huang, X.; Xu, W. M. Tetrahedron Lett. 2002, 43,
5495–5497. (b) Huang, X.; Xie, M. H. Org. Lett. 2002, 4,
1331–1334. (c) Huang, X.; Sun, A. M. J. Org. Chem. 2000, 65,
6561–6565. (d) Huang, X.; Xu, W. M. Org. Lett. 2003, 5,
4649–4652.
4.3.3. Compound 7c. 3-(4-Methyl-phenyl)-5-methyl isoxa-
zole; white solid, mp 57–59 8C; H NMR (CDCl3) d 7.62
1
(2H, d, JZ8.0 Hz), 7.21 (2H, d, JZ8.0 Hz), 6.26 (1H, s),
7. The stereochemistry of obtained olefin is high with excellent
control of Z geometry when unstable Wittig reagent was used,
2.41 (3H, s), 2.35 (3H, s); 13C NMR (CDCl3) d 169.6, 162.5,

506
W. M. Xu et al. / Tetrahedron 61 (2005) 501–506
see: (a) Vedejs, E.; Meier, G. P.; Snoble, K. A. J. J. Am. Chem.
Soc. 1981, 103, 2823–2831. (b) Huang, Y. Z.; Shi, L. L.; Yang,
J. H.; Cai, Z. W. J. Org. Chem. 1987, 52, 3558–3560.
selenide (1.93 g) was obtained as a single product. Yield was
up to 98%.
9. (a) Clive, D. L. J. Tetrahedron 1978, 34, 1049–1095. (b)
Reich, H. J. In Organoselenium Chemistry; Liotta, D., Ed.;
Wiley: New York, 1987.
8. The preparation of phenylpropargyl selenide is described as
follows: diphenyl diselenide (5 mmol) was dissolved in 10 mL
dry THF. To the solution, a mixture of NaBH4 (11 mmol) in
10 mL dry EtOH was slowly added. After stirring at rt for 1 h,
propargyl bromide (12 mmol) was added and stirred at rt for
another 2 h. Extractive workup followed by dryness and
evaporation. Without further purification, phenylpropargyl
10. Corey, E. J.; Jautelat, M. Tetrahedron Lett. 1968, 55,
5787–5788.
11. Shvekhgeimer, G. A.; Baranski, A.; Grzegozek, M. Synthesis
1976, 612–614.