A novel cleavage for polystyrene-supported selenium resins: An efficient route to 3,5-disubstituted isoxazolines and their derivatives

Article abstract of DOI:10.1055/s-2005-869971

We report here a novel cleavage method for polystyrene-supported selenium resin using CH₃I-NaI under mild conditions to prepare 3,5-disubstituted isoxazolines. The polymer selenium resins can be reused without further transformation. Georg Thie

Full text of DOI:10.1055/s-2005-869971

PAPER
2143
A Novel Cleavage for Polystyrene-Supported Selenium Resins: An Efficient
Route to 3,5-Disubstituted Isoxazolines and Their Derivatives
Polystyrene-Supported
S
e
eleniumR
i
R
-
oute to
MSubstituted Isoxazolini
a
Department of Chemistry, Zhejiang University (Campus Xixi), Hangzhou, 310028, P. R. China
Fax +86(571)88807077; E-mail: huangx@mail.hz.zj.cn
b
Center of Analysis and Measurement, Zhejiang University, Hangzhou, 310028, P. R. China
Received 28 February 2005; revised 22 March 2005
We began our efforts from polystyrene-supported selene-
7
nyl bromide (resin 1) (Br: 0.99 mmol/g), which was
Abstract: We report here a novel cleavage method for polystyrene-
supported selenium resin using CH3I–NaI under mild conditions to
prepare 3,5-disubstituted isoxazolines. The polymer selenium res-
ins can be reused without further transformation.
treated with NaBH4 and allyl bromide to give the corre-
sponding pale-yellow resin 2 almost quantitatively (FTIR:
1631 cm–1 and Br was undetectable). Resin 2 reacted
smoothly with nitrile oxides to furnish isoxazoline-sup-
ported selenium resin 3 and in this process we found that
it was necessary to add Et3N dropwise over 24 hours to
avoid the dimerization of the nitrile oxides (Scheme 1).
Keywords: heterocycles, selenium, cycloadditions, isoxazolines,
solid-phase synthesis
The preparation of diverse libraries of organic compounds
is an important facet of modern drug discovery programs.
One of the most commonly employed methods in library
production is solid-phase organic synthesis (SPOS).1 Ex-
perience has shown that compounds with biological activ-
ity are often derived from heterocyclic structures. 1,3-
Dipolar cycloaddition reactions are among the most im-
portant synthetic manipulations allowing the construction
of five-membered ring heterocycles.2 Nitrile oxides have
been shown to be effective 1,3-dipoles and they undergo
smooth reactions with substituted alkynes and alkenes to
give substituted isoxazoles and isoxazolines, respectively.
Se
b
a
SeBr
Se
O
R
N
1
2
3
Scheme 1 (a) (1) NaBH4, THF, DMF, 40 °C, 8 h; (2) allyl bromide,
THF, r.t., 3 h; (b) RCH=NOH, NCS, CH2Cl2, Et3N, r.t., 24 h
Common cleavage protocols of selenium linkers10 have
been reported using two strategies: selenoxide syn-elimi-
nation and radical hydride transfer. Although a b-H exists
in the molecule, selenoxide syn-elimination did not occur
when we treated resin 3 with H2O2 even when we raised
the temperature to 50 °C in THF. n-Bu3SnH could be used
here as a good radical hydride transfer reagent but it was
too toxic. Here we report a new cleavage protocol using
CH3I–NaI in DMF under mild conditions followed by the
method that we11 recently devised under solution condi-
tions (Scheme 2). It shows that 3-substituted 5-(iodo-
methyl)isoxazolines 4 can be obtained in moderate to
good yields with good purity. Results are described in
Table 1.
Isoxazole and isoxazoline moieties represent two classes
of unique pharmacophores that are observed in many ther-
apeutic agents3 and are versatile intermediates for the syn-
thesis of complex natural products.4 It is therefore not
surprising that these structures have received special at-
tention in combinatorial synthesis and several methods for
their preparation have been transferred to the solid phase.5
Since the first organoselenium resin6 was reported in
1976, several groups have developed organoselenium res-
ins as convenient linkers.7,8 Recently, our research group
has been interested in the application of organic selenium
resins in organic synthesis.9 We wish to report here a nov-
el cleavage method, using CH3I–NaI in DMF under mild
conditions, for the isoxazoline supported selenium resin
which is prepared from nitrile oxides and polystyrene-
supported allyl selenide to afford 3-substituted 5-(iodo-
methyl)isoxazolines. Evident advantages of this reaction
are easy operations, odorlessness, and high purity of the
products. And also the resins can be reused without fur-
ther transformation.
Se
I
a
+
SeCH3
O
O
R
R
N
N
3
4
5
Scheme 2 (a) CH3I, NaI, DMF, 80 °C, 24 h
It is noteworthy that polystyrene-supported methyl se-
lenide was regenerated after the cleavage stage without
further transformation. The regenerated polystyrene-sup-
ported methyl selenide7 could be reused as a starting ma-
terial and recycled in the same reaction for several times
without the loss of purity of the products but with a slight
decrease in yield. Results are described in Table 2.
SYNTHESIS 2005, No. 13, pp 2143–2146
x
x.
x
x
.
2
0
0
5
Advanced online publication: 24.06.2005
DOI: 10.1055/s-2005-869971; Art ID: F04505SS
© Georg Thieme Verlag Stuttgart · New York

2144
W.-M. Xu et al.
PAPER
Starting materials were obtained from commercial suppliers and
used without further purification. DMF was distilled from calcium
hydride and THF was distilled from sodium–benzophenone imme-
diately prior to use. Polystyrene (H 1000, 100-200 mesh, cross-
linked with 1% divinylbenzene) was purchased from commercial
Table 1 Synthesis of 3,5-Disubstituted Isoxazolines
Products
R
Yield (%)a
Purity b
96
4a
4b
4c
4d
4e
4f
4-FC6H4
4-NO2C6H4
4- BrC6H4
4-ClC6H4
4-CH3C6H4
COOEt
Ph
77
71
78
82
80
87
78
1
sources. H NMR (400 MHz) and 13C NMR (100 MHz) spectra
89
were recorded on a Bruker Avance (400 MHz) spectrometer, using
CDCl3 as the solvent and TMS as internal standard. MS (EI, 70eV)
were recorded on a HP5989B mass spectrometer. IR spectra were
recorded on a Shimadzu IR-408 spectrometer. Elemental analyses
were performed on a Flash EA1112 instrument. HPLC was per-
formed on an Agilernt 1100 high performance liquid chromato-
graph.
97
95
98
98
Polystyrene-Supported Selenenyl Bromide 1; Typical
Procedure7
4g
95
a Yield of the crude product based on the loading of the resin 1.
b Determined by HPLC.
To a suspension of swollen polystyrene-supported methyl selenide
(Se: 1.08 mmol/g) (2.5 g) in anhyd CH2Cl2 (40 mL) was dropwise
added Br2 (2.7 mmol in 10 mL anyhyd CH2Cl2) under nitrogen at-
mosphere at 0 °C. After stirring at 0 °C for 30 min, the resin was
collected by filtration, washed with CH2Cl2 (20 mL × 2) and EtOH
(20 mL × 2), and reswelled in EtOH (50 mL). The mixture was
stirred at 65 °C for 1 h. After the reaction, the resin 1 was collected
by filtration and dried under vacuum.
Table 2 Recycling of the Polymer Selenium Resin
Preparation of Isoxazoline-Supported Selenium Resin 3; Typi-
cal Procedure
Products
Times
Yield (%)a
Purity b
98
4e
4e
4e
4e
1
2
3
4
78
77
75
73
To a suspension of the swollen polystyrene-supported selenenyl
bromide (Br: 0.99 mmol/g) resin 1 (2.5 g) in anhyd THF–DMF (5:1;
30 mL) was added NaBH4 (5 mmol) under a nitrogen atmosphere at
40 °C. After stirring for 8 h at 40 °C, allyl bromide (5.5 mmol) was
added dropwise under a nitrogen atmosphere, and stirring was con-
tinued for another 3 h. The resin 2 was collected by filtration,
washed with THF (20 mL × 2), THF–H2O (3:1; 20 mL × 2), H2O
(20 mL × 2), THF (20 mL × 2), and CH2Cl2 (20 mL × 2), and dried
under vacuum. To a suspension of the swollen resin 2 (2.5 g) in
CH2Cl2 was added a mixture of hydroximoyl halide (7.5 mmol) in
CH2Cl2 (10 mL; prepared from 7.5 mmol of aldoxime and 7.5 mmol
of NCS stirring at r.t. for about 3 h before use). A mixture of Et3N
(9 mmol) in CH2Cl2 (15 mL) was slowly added dropwise in 3 por-
tions every 8 h (each time 3 mmol in 5 mL anhyd CH2Cl2 was add-
ed). After stirring for 24 h at r.t., the resin 3 was collected by
filtration, washed with THF (20 mL × 2), Et2O (20 mL × 2), THF–
H2O (3:1) (20 mL × 2), THF (20 mL × 2), benzene (20 mL × 2),
MeOH (20 mL × 2), and CH2Cl2 (20 mL × 2), and dried under vac-
uum.
96
96
96
a Yield of the crude product based on the original loading of the
resin 1.
b Determined by HPLC.
An outstanding feature of this cleavage reaction is that a
new functional group (iodine) is introduced during the
cleavage stage, which has versatile reactivities in organic
synthesis. 3-Substituted 5-(iodomethyl)isoxazolines 4 re-
acted with an organic base (DBU) or an inorganic base
(NaCN) to afford 3-substituted 5-methylisoxazole 6 al-
most quantitatively and also they reacted with p-
MeC6H4SO2Na to afford 3,5-disubstituted isoxazoline 7
in moderate yield (Scheme 3).
Preparation of 3-Substituted 5-Iodomethyl Isoxazolines; Gen-
eral Procedure
To a suspension of the swollen resin 3 (0.5 g) in anhyd DMF (5 mL),
was added NaI (1.0 g) and CH3I (1.0 mL) under nitrogen. The sus-
pension was stirred at 80 °C for 24 h. The mixture was filtered and
the resin was washed with CH2Cl2 (10 mL × 3). The filtrate was
washed successively with sat. aq NaHCO3 (30 mL), sat. aq Na2S2O3
(30 mL) and H2O (30 mL × 3), dried (MgSO4), and evaporated to
dryness under vacuum.
SO2C6H4CH3-pm
I
a
b
O
O
O
R
N
R
N
R
N
7
4
6
R = 4-CH3C6H4 Yield >95%
R = 4-FC6H4 Yield = 68%
Scheme 3 (a) DBU or NaCN, DMF, 80 °C, 12 h; (b) PhSO2Na,
DMF, 130 °C, 16 h
3-(4-Fluorophenyl)-5-iodomethylisoxazoline (4a)
White solid; mp; 88–89 °C.
IR: 1630, 1599, 1492, 897, 819, 540 cm–1.
1H NMR (CDCl3): d = 7.70–7.66 (2 H, m), 7.12 (2 H, t, J = 8.8 Hz),
4.96–4.92 (1 H, m), 3.52 (1 H, dd, J1 = 10.4, J2 = 16.8 Hz), 3.44 (1
cleavage protocol of selenium resin. It is noteworthy that H, dd, J1 = 4.0, J2 = 10.4 Hz), 3.28–3.19 (2 H, m).
In conclusion, we have developed a method for the prep-
aration of 3,5-disubstituted isoxazoles through a novel
13C NMR (CDCl3): d = 163.9 (J = 249.6 Hz), 154.8, 126.7 (J = 8.4
Hz), 125.4 (J = 5.8 Hz), 115.9 (J = 22.3 Hz), 80.5, 41.1, 7.3.
the polymer selenium resins used here can be recycled
without further transformation.
MS: m/z = 178 (40), 305 (100, M+)
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PAPER
Polystyrene-Supported Selenium Resins: Route to Substituted Isoxazolines
2145
Anal. Calcd for C10H9FINO: C, 39.25; H, 2.87; N, 4.68. Found: C,
39.37; H, 2.97; N, 4.59.
13C NMR (CDCl3): d = 160.3, 150.8, 82.6, 62.2, 39.7, 14.1, 6.0.
MS: m/z = 91 (100), 283 (74, M+).
Anal. Calcd for C7H10INO3: C, 29.81; H, 3.61; N, 4.88. Found: C,
29.70; H, 3.56; N, 4.95.
3-(4-Nitrophenyl)-5-iodomethylisoxazoline (4b)
White solid; mp 123–124 °C.
IR: 1630, 1598, 1511, 1340, 1319, 909, 751, 690 cm–1.
3-Phenyl-5-iodomethylisoxazoline (4g)
Low-melting solid.
1H NMR (CDCl3): d = 8.26 (2 H, d, J = 8.0 Hz), 7.82 (2 H, d,
J = 8.0 Hz), 4.99–4.90 (1 H, m), 3.53 (1 H, dd, J1 = 10.8, J2 = 17.2
Hz), 3.43 (1 H, dd, J1 = 4.0, J2 = 10.0 Hz), 3.28–3.20 (2 H, m).
IR: 1631, 1600, 1495, 1108, 892, 758, 693, 540 cm–1.
1H NMR (CDCl3): d = 7.69–7.67 (2 H, m), 7.43–7.41 (3 H, m),
4.97–4.90 (1 H, m), 3.53 (1 H, dd, J1 = 10.0, J2 = 16.8 Hz), 3.43 (1
H, dd, J1 = 4.0, J2 = 10.0 Hz), 3.27–3.21 (2 H, m).
13C NMR (CDCl3): d = 154.2, 135.1, 127.4, 126.0, 124.0, 81.3, 40.5,
6.8.
MS: m/z = 332 (100, M+).
13C NMR (CDCl3): d = 155.0, 132.0, 128.6, 128.2, 124.7, 80.7, 40.8,
7.3.
Anal. Calcd for C10H9IN2O3: C, 36.29; H, 2.79; N, 8.36. Found: C,
36.17; H, 2.73; N, 8.44.
MS: m/z = 91 (100), 287 (89, M+).
Anal. Calcd for C10H10INO: C, 41.93; H, 3.44; N, 4.95. Found: C,
41.83; H, 3.51; N, 4.88.
3-(4-Bromophenyl)-5-iodomethylisoxazoline (4c)
White solid; mp 116–117 °C.
1H NMR (CDCl3): d = 7.54 (4 H, s), 4.96–4.92 (1 H, m), 3.49 (1 H,
dd, J1 = 10.8, J2 = 16.8 Hz), 3.44 (1 H, dd, J1 = 4.0, J2 = 10.0 Hz),
3.26–3.17 (2 H, m).
3-(4-Methylphenyl)-5-methylisoxazole (6)
3-(4-Methylphenyl)-5-iodomethylisoxazoline (0.3 mmol) was dis-
solved in DMF–THF (5 mL; 2:3), and to the mixture DBU (0.5
mmol) was added. The mixture was stirred at 90 °C for 10 h. After
the reaction, CH2Cl2 (20 mL) was added. The mixture was washed
with sat. aq NaHCO3 (20 mL) and H2O (15 mL × 3) and dried
(MgSO4). Drying without further purification gave 6 as a single
product.
13C NMR (CDCl3): d = 155.0, 132.0, 128.2, 124.7, 80.7, 40.8, 7.3.
MS: m/z = 75 (100), 365 (82, M+).
IR: 1629, 1598, 1493, 1102, 896, 821 cm–1.
Anal. Calcd for C10H9BrINO: C, 32.93; H, 2.57; N, 3.78. Found C,
32.82; H, 2.48; N, 3.83.
White solid; 50.9 mg; mp 57–59 °C.
IR: 3058, 1622, 1599, 1378, 1222, 829 cm–1.
3-(4-Chlorophenyl)-5-iodomethylisoxazoline (4d)
White solid; mp 91–91.5 °C.
1H NMR (CDCl3): d = 7.62 (2 H, d, J = 8.0 Hz), 7.21 (2 H, d,
J = 8.0 Hz), 6.26 (1 H, s), 2.41 (3 H, s), 2.35 (3 H, s).
IR: 1631, 1596, 1495, 1098, 892, 826, 612, 543 cm–1.
13C NMR (CDCl3): d = 169.6, 162.5, 140.0, 129.5, 126.6, 126.5,
99.6, 21.3, 12.3.
1H NMR (CDCl3): d = 7.67 (2 H, d, J = 8.4 Hz), 7.45 (2 H, d,
J = 8.4 Hz), 5.02–4.96 (1 H, m), 3.57 (1 H, dd, J1 = 10.4, J2 = 16.8
Hz), 3.48 (1 H, dd, J1 = 4.0, J2 = 10.0 Hz), 3.32–3.23 (2 H, m).
MS: m/z = 173 (100, M+).
13C NMR (CDCl3): d = 154.8, 136.3, 129.0, 127.9, 127.6, 80.6, 40.9,
7.2.
Anal. Calcd for C11H11NO: C, 76.28; H, 6.40; N, 8.09. Found: C,
76.39; H, 6.49; N, 7.97.
MS: m/z = 152 (100), 321 (99, M+).
3-(4-Fluorophenyl)-5-para-toluenesulfonylmethylisoxazoline
(7)
Anal. Calcd for C10H9ClINO: C, 37.26; H, 2.88; N, 4.28. Found C,
37.35; H, 2.82; N, 4.36.
3-(4-Fluorophenyl)-5-iodomethylisoxazoline (0.3 mmol) was dis-
solved in DMF (5 mL), and to the mixture p-MeC6H4SO2Na (0.9
mmol) was added. The mixture was stirred at 130 °C for 10 h. After
the reaction, CH2Cl2 (20 mL) was added. The mixture was washed
with sat. aq NaHCO3 (20 mL) and H2O (15 mL × 3) and dried
(MgSO4). Drying followed by purification via flash chromatogra-
phy (n-hexanes–EtOAc, 4:1) gave 7.
3-(4-Methylphenyl)-5-iodomethylisoxazoline (4e)
White solid; mp 86–87 °C.
IR: 1632, 1599, 1580, 1495, 1377, 898, 816 cm–1.
1H NMR (CDCl3): d = 7.56 (2 H, d, J = 8.0 Hz), 7.22 (2 H, d,
J = 8.0 Hz), 4.92–4.90 (1 H, m), 3.50 (1 H, dd, J1 = 10.4, J2 = 16.8
Hz), 3.42 (1 H, dd, J1 = 4.0, J2 = 10.0 Hz), 3.25–3.19 (2 H, m), 2.38
(3 H, s).
White solid; 67.9 mg; mp 147–148 °C.
IR: 1627, 1599, 1495, 1319, 1146, 891, 822 cm–1.
13C NMR (CDCl3): d = 155.7, 140.6, 129.4, 126.7, 126.3, 80.3, 41.1,
21.4, 7.5.
1H NMR (CDCl3): d = 7.72 (2 H, d, J = 8.0 Hz), 7.57–7.53 (2 H, m),
7.30 (2 H, d, J = 8.0 Hz), 7.00 (2 H, t, J = 7.6 Hz), 5.02–4.97 (1 H,
m), 3.54–3.40 (2 H, m), 3.37 (1 H, dd, J1 = 6.4, J2 = 17.6 Hz), 3.26
(1 H, dd, J1 = 10.4, J2 = 13.2 Hz), 2.38 (3 H, s).
MS: m/z = 91 (100), 301 (74, M+).
Anal. Calcd for C11H12INO: C, 43.99; H, 3.94; N, 4.58. Found: C,
43.87; H, 4.02; N, 4.65.
MS: m/z = 164 (100), 333 (M+).
Anal. Calcd for C17H16FNO3S: C, 61.38; H, 4.89; N, 4.11. Found:
C, 61.25; H, 4.84; N, 4.20.
3-Ethoxycarbonyl-5-iodomethylisoxazoline (4f)
White solid; mp; 77–78 °C.
IR: 1720, 1631, 1591, 1259, 930, 862, 617 cm–1.
Acknowledgement
1H NMR (CDCl3): d = 4.97–4.93 (1 H, m), 4.36 (2 H, q, J = 7.2
Hz), 3.41–3.34 (2 H, m), 3.22 (1 H, t, J = 9.2 Hz), 3.09 (1 H, dd,
J1 = 7.2, J2 = 18.2 Hz), 1.38 (3 H, d, J = 7.2 Hz).
We are grateful to the Natural Science Foundation of China (Project
No.20332060 and 20272050) and the CAS Academician Founda-
tion of Zhejiang Province.
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Synthesis 2005, No. 13, 2143–2146 © Thieme Stuttgart · New York