Tandem synthesis of 3-chloro-4-iodoisoxazoles from 1-Copper(I) alkynes, dichloroformaldoxime, and molecular iodine

Article abstract of DOI:10.1021/jo502634h

A tandem synthesis for structurally novel 3-chloro-4-iodoisoxazoles was developed by simply mixing 1-copper(I) alkynes, dichloroformaldoxime, and molecular iodine together. The combination of 1-copper(I) alkyne and molecular iodine was well used as a synthetic equivalent of 1-iodoalkyne without the need for tedious preparation, purification, and storage of 1-iodoalkyne.

Full text of DOI:10.1021/jo502634h

Note
pubs.acs.org/joc
Tandem Synthesis of 3‑Chloro-4-iodoisoxazoles from 1‑Copper(I)
Alkynes, Dichloroformaldoxime, and Molecular Iodine
Wenwen Chen, Jianlan Zhang, Bo Wang, Zhouxing Zhao, Xinyan Wang,* and Yuefei Hu*
Department of Chemistry, Tsinghua University, Beijing 100084, P. R. China
*
S Supporting Information
ABSTRACT: A tandem synthesis for structurally novel 3-chloro-4-
iodoisoxazoles was developed by simply mixing 1-copper(I) alkynes,
dichloroformaldoxime, and molecular iodine together. The combina-
tion of 1-copper(I) alkyne and molecular iodine was well used as a
synthetic equivalent of 1-iodoalkyne without the need for tedious preparation, purification, and storage of 1-iodoalkyne.
soxazoles are important heterocycles found in numerous
natural products and synthetic compounds. Their novel
biological properties have made them a focus of medicinal
chloro-4-iodoisoxazoles (1) from 1-Cu(I) alkynes (2), dichloro-
formaldoxime (Cl CNOH, 3), and I under extremely simple
conditions.
1
I
2
2
chemistry. As shown in Figure 1, broxaterol (as a β -selective
There are three types of methods for the synthesis of 4-
iodoisoxazoles which can be categorized by the substrates
2
6
employed: (a) direct iodination of 4-H-isoxazoles; (b) electro-
7
philic cyclization of α-alkynyl oximes; (c) 1,3-dipolar cyclo-
additions of special alkynes (such as 1-iodo- or 1-alumino-
8
alkynes) with nitrile oxides. Since 1,3-dipolar cycloadditions of
alkynes with chloronitrile oxide [Cl−CN→O, generated in
Figure 1. Structures of broxaterol and valdecoxib.
situ by dehydrochlorination of Cl CNOH (3)] was the only
2
practical method for introduction of a Cl-atom into the 3-
2
8c
agonist) was developed to be an orally active antiasthmatic drug.
position of isoxazole ring, the procedure reported by Browne
Valdecoxib (as a selective inhibitor of COX-2) was a drug for the
treatment of osteoarthritis, rheumatoid arthritis, and primary
dysmenorrhea.
was initially tested for our purpose. It is well-known that the 1,3-
dipolar cycloadditions usually have two common drawbacks
caused by the extremely high reactivity of nitrile oxide: poor
3
1
,5,9
Possibly encouraged by the discovery of broxaterol, 3-
haloisoxazoles have been popular synthetic targets over the
years. Many methods have been developed for their synthesis to
regiocontrol of products and dimerization of nitrile oxide.
These drawbacks were partially overcome in Browne’s procedure
by adding aqueous Na CO with a syringe pump, by which the
2
3
4
,5
increase the diversity of structures and properties. Recently, 4-
iodoisoxazoles have become attractive synthetic targets for their
wide uses as versatile substrates. As shown in Figure 2, they can
be smoothly converted into the corresponding 4-aryl, 4-alkenyl,
formation rate of nitrile oxide was controlled. As shown in
Scheme 1, when we followed Browne’s procedure to treat the
Scheme 1
6
−8
or 4-alkynylisoxazoles by metal-catalyzed cross-couplings.
In our recent chemical biology project, a variety of 3-
chloroisoxazoles were required and 3-chloro-4-iodoisoxazoles
(
1) were assigned as key precursors. To our great surprise, such
precursors represent a structurally new type of compound that,
to the best of knowledge, has yet to appear in the literature.
Herein, we would like to report a novel tandem synthesis of 3-
mixture of 3 and 1-iodo-2-phenylethyne (4) with aqueous
Na CO without using the syringe pump modification, the
2
3
desired compound 1a was isolated in 18% yield from a mixture
with dimer 5 as a major byproduct.
Realizing many 1,3-dipolar cycloadditions using 1-iodoalkyne
10
as a dipolarophile could be catalyzed by Cu(I)-catalysts, the
1
0i
catalytic system CuI/Et N
was tested in our reaction.
3
Unfortunately, the lower yield of 1a (9%) was obtained when
Received: November 18, 2014
Figure 2. 4-Iodoisoxazoles as versatile substrates.
©
XXXX American Chemical Society
A
DOI: 10.1021/jo502634h
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
a
the mixture of 3 and 4 was treated with CuI/Et N (Scheme 2).
Table 1. Effect of the Ratios of 3, 2a, and I on the Yield of 1a
3
2
The problem may be caused by the fact that Et N may function as
3
Scheme 2
b
entry
3:2a:I (mole ratio)
1a (%)
2
1
2
3
4
5
6
7
1.0:1.0:1.0
1.0:1.0:1.2
1.0:1.0:1.5
1.2:1.0:1.0
1.5:1.0:1.0
1.0:1.2:1.0
1.0:1.5:1.0
74
60
29
60
63
94
95
both a ligand and a base, because a large amount of dimer 5 was
separated. However, the same reaction gave a trace of 1a when
Et N was replaced with powdered NaHCO . To our delight, the
a
The mixture of 3, 2a, I
mL) was stirred in a stoppered glass tube. The isolated yields.
, and NaHCO (1 mmol, 2 equiv) in DMF (1
3
b
2
3
3
yield of 1a increased to 77% yield when a stoichiometric amount
of CuI was employed. These results may arise from the fact that
the catalytic cycle of Cu(I) may be inhibited in the absence of a
As shown in Scheme 4, a tandem pathway was proposed for
this novel method. First, 2a reacts with I to quantitatively
2
10i,11
ligand.
In further experiments, we found that the preparation of 1-
iodoalkynes was the main obstacle to generalize this method. In
the literature, many methods have been reported to convert
terminal alkynes into the corresponding 1-iodoalkynes under
mild conditions (without using strong bases or air sensitive
Scheme 4
10i,12
reagents),
but the special iodination reagents and tedious
workup processes were essential to each of them. Since 1-
iodoalkynes normally are sensitive to air and light, they tend to
darken caused by decomposition during preparation, purifica-
13
tion, and storage. In our recent work, 1-iodo-2-phenyethyne
(
4) was accidentally obtained in 98% yield by simply mixing 1-
14
Cu(I) phenyethyne (2a) and NIS in CH Cl within 10 min.
2
2
Thus, we were encouraged to test the same conversion by using
+
I as a source of I in DMF, and similarly excellent results were
2
produce 4 and CuI. Then, the triple bond of 4 is activited by
obtained (Scheme 3). Since this conversion clearly produces
equimolar amounts of 4 and CuI only, the desired 1a may be
10a,b
coordination with Cu(I).
Finally, the activated 4 as a
dipolarophile undergoes a 1,3-dipolar cycloaddition with α-
chloronitrile oxide to give the desired 1a. Since 1-Cu(I) alkynes
synthesized by simply adding 3 and NaHCO into this reaction
3
system.
1
5,6d,17a
1
usually can be prepared as yellow crystals within 1 h
and
5−17
stored in air over one year without notable decomposition,
Scheme 3
the combination of 1-Cu(I) alkyne and I could be well used as a
2
synthetic equivalent of 1-iodoalkyne, but without the need for
tedious separation, purification, and storage.
To generalize this method, the scope of substrates was tested.
As shown in Scheme 5, all products (1a−1t) were obtained in
good to excellent yields. The steric effects have significant
influences on the arylethynes bearing electron-donating groups
(
see: 1b−1d), but almost no influences on those bearing
electron-withdrawing groups (see: 1f−1h). The arylethynes
usually gave the products in higher yields (see: 1a−1k)
compared to the alkylethynes (see: 1l−1s). When 1-Cu(I)-2-
isopropenylethyne (2t) was used as a substrate, both its triple and
double bonds underwent the corresponding 1,3-dipolar cyclo-
additions to give the expected product 1t containing both
isoxazole and isoxazoline rings. The structure of 1a was further
confirmed by its single crystal X-ray diffraction analysis (see
Supporting Information (SI)).
As shown in Table 1, the desired 1a was obtained in 74% yield
when 3, 2a, I , and NaHCO were mixed together in DMF for 6 h
2
3
(
entry 1), which matched well with the result obtained from the
premade substrate 4. It was interesting to observe that this
reaction was influenced significantly by the ratio of the reactants.
The yield of 1a was decreased by increasing the ratio of I (entries
2
2
and 3), which may be caused by the oxidative property of I2
because the oxidative coupling product 1,4-diphenylbutadiyne
was separated. Similarly, the yield of 1a was also decreased by
using an excess of 3 (entries 4 and 5). To our delight, 1a was
obtained in 94% yield when 1.2 equiv of 2a was used (entry 6).
But, no significant improvement was observed by using a higher
ratio of 2a (entry 7). Thus, entry 6 was assigned as our standard
conditions.
As was expected, the iodine atom in 1a was smoothly
converted into the corresponding aryl, alkenyl, or alkynyl groups
7
d
7d
6f
under Suzuki, Heck, or Sonogashira cross-coupling
conditions, while the chlorine atom stayed intact (Scheme 6).
In practice, these structurally novel products could not be
synthesized easily by other routine methods.
B
DOI: 10.1021/jo502634h
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
mg, 0.5 mmol) in DMF (1 mL) was added dichloroformaldoxime (3, 57
mg, 0.5 mmol) at room temperature. After the resultant suspension was
stirred for 10 min, a red homogeneous solution was formed. The
reaction system was converted into a deep red-brown solution at the end
point [6 h, monitored by TLC, the in situ generated 1-iodo-2-
phenylethyne (4) was exhausted]. The reaction mixture was allowed to
directly pass through a column [silica gel, 2% EtOAc in petroleum ether
Scheme 5
(
60−90 °C)] to give 143 mg (94%) of product 1a as a white solid, mp
−1 1
9
8
1
1−92 °C. IR ν 2922, 1555, 1434, 1330 cm ; H NMR (400 MHz) δ
13
.04−8.03 (m, 2H), 7.53−7.51 (m, 3H); C NMR (100 MHz) δ 169.8,
58.5, 131.3, 128.9 (2C), 127.2 (2C), 126.4, 57.7; HRMS (ESI-TOF)
+
(
m/z): calcd for C H ClINO, [M + H] 305.9177; found 305.9182.
9
5
Anal. Calcd for C H ClINO: C, 35.38; H, 1.65; N, 4.58. Found: C,
9
5
3
5.43; H, 1.69; N, 4.49.
The products 1b−1t were prepared by the similar method.
3-Chloro-4-iodo-5-(4-tolyl)isoxazole (1b). White solid (134 mg,
−1 1
8
4%), mp 80−81 °C. IR ν 2923, 1496, 1333 cm ; H NMR (400 MHz)
13
δ 7.93 (d, J = 8.2 Hz, 2H), 7.32 (d, J = 8.2 Hz, 2H), 2.43 (s, 3H);
C
NMR (75 MHz) δ 170.0, 158.4, 141.9, 129.6 (2C), 127.2 (2C), 123.7,
+
5
7.0, 21.6; HRMS (ESI-TOF) (m/z): calcd for C H ClINO, [M + H]
10 7
3
19.9334; found 319.9331.
-Chloro-4-iodo-5-(3-tolyl)isoxazole (1c). White solid (131 mg,
3
−1 1
8
2%), mp 62−63 °C. IR ν 2920, 1545, 1437, 1322 cm ; H NMR (400
13
MHz) δ 7.86−7.84 (m, 2H), 7.43−7.34 (m, 2H), 2.45 (s, 3H);
NMR (100 MHz) δ 170.0, 158.5, 138.8, 132.1, 128.8, 127.7, 126.4,
C
1
+
24.4, 57.6, 21.4; HRMS (ESI-TOF) (m/z): calcd for C H ClINO, [M
10 7
+
H] 319.9334; found 319.9335.
-Chloro-4-iodo-5-(2-tolyl)isoxazole (1d). White solid (115 mg,
3
−1 1
7
2%), mp 61−62 °C. IR ν 2926, 1547, 1445, 1329 cm ; H NMR (400
13
MHz) δ 7.47−7.42 (m, 2H), 7.35−7.30 (m, 2H), 2.36 (s, 3H);
NMR (75 MHz) δ 173.5, 157.8, 138.0, 131.3, 131.0, 130.1, 126.1, 125.9,
C
+
6
1.7, 20.2; HRMS (ESI-TOF) (m/z): calcd for C H ClINO, [M + H]
10 7
3
19.9334; found 319.9333.
3-Chloro-4-iodo-5-(4-ethylphenyl)isoxazole (1e). White solid
Scheme 6
−1 1
(
127 mg, 76%), mp 50−52 °C. IR ν 2926, 1611, 1443, 1331 cm ; H
NMR (400 MHz) δ 7.95 (d, J = 7.8 Hz, 2H), 7.34 (d, J = 8.2 Hz, 2H),
13
2
.72 (q, J = 7.8 Hz, 2H), 1.28 (t, J = 7.8 Hz, 3H); C NMR (100 MHz) δ
1
70.0, 158.4, 148.1, 128.4 (2C), 127.2 (2C), 123.9, 57.0, 28.9, 15.2;
+
HRMS (ESI-TOF) (m/z): calcd for C H ClINO, [M + H] 333.9490;
11
9
found 333.9490.
3
-Chloro-4-iodo-5-(4-fluorophenyl)isoxazole (1f). White solid
−1 1
(
149 mg, 92%), mp 87−88 °C. IR ν 2924, 1598, 1498, 1329 cm ; H
13
NMR (400 MHz) δ 8.07−8.04 (m, 2H), 7.26−7.20 (m, 2H); C NMR
100 MHz) δ 169.0, 164.3 (d, J = 252.7 Hz), 158.6, 129.5 (d, J = 8.6 Hz,
C), 122.7 (d, J = 3.8 Hz), 116.2 (d, J = 21.9 Hz, 2C), 57.6. HRMS (ESI-
(
2
−
TOF) (m/z): calcd for C H ClFINO, [M − H] 321.8937; found
9
4
3
21.8941.
-Chloro-4-iodo-5-(3-fluorophenyl)isoxazole (1g). White solid
146 mg, 90%), mp 106−107 °C. IR (KBr) ν 3078, 1553, 1444, 1329
3
(
−
1 1
cm ; H NMR (400 MHz) δ 7.87−7.75 (m, 2H), 7.54−7.48 (m, 1H),
13
In summary, a tandem synthesis of 3-chloro-4-iodo-isoxazoles
was developed from 1-Cu(I) alkynes, dichloroformaldoxime, and
I2. The final results of this method appeared to involve a Cu(I)-
catalyzed 1,3-dipolar cycloaddition by using 1-iodoalkynes as a
dipolarophile. However, it not only avoided the tedious
preparation, purification, and storage of 1-iodoalkyne but also
avoided use of a syringe pump in the experimental operations.
Since the method proceeded under extremely convenient
conditions and the products have entirely new structures, they
may have wide applications in organic synthesis and drug
discovery.
7
.26−7.22 (m, 1H); C NMR (100 MHz) δ 168.4, 162.6 (d, J = 246.0
Hz), 158.7, 130.7 (d, J = 8.6 Hz), 128.2 (d, J = 8.6 Hz), 122.9 (d, J = 2.9
Hz), 118.4 (d, J = 21.0 Hz), 114.2 (d, J = 23.8 Hz), 58.7. HRMS (ESI-
−
TOF) (m/z): calcd for C H ClFINO, [M − H] 321.8937; found
9
4
3
21.8939.
-Chloro-4-iodo-5-(2-fluorophenyl)isoxazole (1h). White solid
3
−1 1
(
147 mg, 91%), mp 94−96 °C. IR ν 2921, 1617, 1468, 1331 cm ; H
NMR (300 MHz) δ 7.69−7.64 (m, 1H), 7.60−7.52 (m, 1H), 7.34−7.22
13
(m, 2H); C NMR (75 MHz) δ 168.4, 159.4 (d, J = 253.8 Hz), 158.3,
1
1
33.4 (d, J = 7.9 Hz), 130.6, 124.5 (d, J = 3.6 Hz), 116.8 (d, J = 20.8 Hz),
14.9 (d, J = 13.6 Hz), 62.4. HRMS (ESI-TOF) (m/z): calcd for
−
C H ClFINO, [M − H] 321.8937; found 321.8935.
9
4
3
-Chloro-4-iodo-5-(4-nitrophenyl)isoxazole (1i). Yellowish
−1
EXPERIMENTAL SECTION
All spectra of H and C NMR were recorded in CDCl , and TMS was
used as an internal reference. 1-Copper(I) alkynes (2a−2t) were
prepared by reported procedures in literature.
solid (145 mg, 83%), mp 156−158 °C. IR ν 3119, 1515, 1340 cm ;
■
1
1
13
H NMR (400 MHz) δ 8.40 (d, J = 9.2 Hz, 2H), 8.28 (d, J = 8.7 Hz, 2H);
3
13
C NMR (100 MHz) δ 167.3, 159.1, 149.0, 131.8, 128.0 (2C), 124.2
15,16d,17a
(2C), 60.8; HRMS (ESI-TOF) (m/z): calcd for C
H] 348.8882; found 348.8877.
H
9
ClIN
O
, [M −
3
4
2
−
A Typical Procedure for the Synthesis of 3-Chloro-4-iodo-5-
phenylisoxazole (1a). To a suspension of 1-copper(I)-2-phenyl-
ethyne (2a, 99 mg, 0.6 mmol), NaHCO (84 mg, 1.0 mmol), and I (127
3-Chloro-4-iodo-5-(4-chlorophenyl)isoxazole (1j). White solid
−1 1
(158 mg, 93%), mp 103−105 °C. IR ν 2922, 1586, 1474, 1327 cm ; H
3
2
C
DOI: 10.1021/jo502634h
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
NMR (400 MHz) δ 7.98 (d, J = 8.3 Hz, 2H), 7.49 (d, J = 8.7 Hz, 2H);
C NMR (75 MHz) δ 168.6, 158.6, 137.5, 129.2 (2C), 128.3 (2C),
CH Cl (3 × 15 mL). The combined organic layers were washed with
2
2
1
3
brine (15 mL) and dried over Na SO . The solvent was removed on a
2 4
1
24.7, 58.1; HRMS (ESI-TOF) (m/z): calcd for C H Cl INO, [M +
rotavapor, and the residue was purified by flash chromatography [silica
gel, 4% EtOAc in petroleum ether (60−90 °C)] to give 142 mg (94%) of
6 as a white solid, mp 118−119 °C. IR (KBr) ν 3070, 1632, 1529, 1391
9
4
2
+
H] 339.8787; found 339.8783.
-Chloro-4-iodo-5-(4-bromophenyl)isoxazole (1k). White
solid (175 mg, 91%), mp 101−103 °C. IR ν 3086, 1584, 1479, 1327
3
−
1 1
cm ; H NMR (400 MHz) δ 8.32−8.27 (m, 2H), 7.72−7.64 (m, 2H),
−1
1
13
cm ; H NMR (400 MHz) δ 7.92 (d, J = 8.2 Hz, 2H), 7.67 (d, J = 8.7
7.52−7.50 (m, 2H), 7.48−7.45 (m, 1H), 7.41−7.37(m, 2H); C NMR
13
Hz, 2H); C NMR (100 MHz) δ 168.8, 158.7, 132.3 (2C), 128.6 (2C),
(100 MHz) δ 167.6, 153.5, 148.7, 136.0, 131.2, 130.2, 129.9, 129.1 (2C),
127.0 (2C), 126.2, 124.9, 123.7, 113.0. HRMS (ESI-TOF) (m/z): calcd
1
26.0, 125.3, 58.2; HRMS (ESI-TOF) (m/z): calcd for C H BrClINO,
9
4
−
+
[
M − H] 381.8137; found 381.8123.
for C H ClN O , [M + H] 301.0374; found 301.0376. Anal. Calcd for
15
9
2
3
3
-Chloro-4-iodo-5-isopentyl-isoxazole (1l). Colorless oil (141
C H ClN O : C, 59.91; H, 3.02; N, 9.32. Found: C, 59.80; H, 3.13; N,
15 9 2 3
−1 1
mg, 94%). IR ν 2959, 2871, 1578, 1462, 1345 cm ; H NMR (400
MHz) δ 2.80 (t, J = 7.4 Hz, 2H), 1.62−1.58 (m, 3H), 0.95 (d, J = 6.4 Hz,
9
.47.
Synthesis of Methyl (E)-3-(3-Chloro-5-phenyl-isoxazol-4-yl)-
H); 13C NMR (100 MHz) δ 176.4, 157.1, 59.4, 35.6, 27.5, 25.5, 22.1
7d
6
acrylate (7). After the mixture of 1a (153 mg, 0.5 mmol), Na CO
2 3
+
(
2C). HRMS (ESI-TOF) (m/z): calcd for C H ClINO, [M + H]
(133 mg, 1.25 mmol), n-Bu NCl (139 mg, 0.5 mmol), Pd(OAc) (11
4 2
8
11
2
99.9647; found 299.9633.
-Chloro-4-iodo-5-heptyl-isoxazole (1m). Colorless oil (136
mg, 0.05 mmol), and methyl acrylate (172 mg, 2.0 mmol) in DMF (2
mL) in a Schlenk tube was degassed, it was stirred for 24 h at 85 °C
under N . Then the resultant mixture was poured into H O (15 mL) and
3
−1 1
mg, 87%). IR ν 2928, 1578, 1460, 1346 cm ; H NMR (400 MHz) δ
.80 (t, J = 7.8 Hz, 2H), 1.74−1.67 (m, 2H), 1.38−1.26 (m, 6H), 0.89 (t,
2
2
2
was extracted with CH Cl (3 × 15 mL). The combined organic layers
2
2
13
J = 6.8 Hz, 3H); C NMR (100 MHz) δ 176.3, 157.1, 59.6, 31.2, 28.6,
were washed with brine (15 mL) and dried over Na SO . The solvent
2
4
2
7.5, 26.9, 22.4, 14.0. HRMS (ESI-TOF) (m/z): calcd for C H ClINO,
9
13
was removed on a rotavapor, and the residue was purified by flash
chromatography [silica gel, 4% EtOAc in petroleum ether (60−90 °C)]
to give 118 mg (90%) of 7 as white solid, mp 80−81 °C. IR ν 2953, 1644,
+
[
M + H] 313.9803; found 313.9805.
-Chloro-4-iodo-5-cyclohexyl-isoxazole (1n). Colorless oil (115
3
−1 1
mg, 74%). IR ν 2933, 1570, 1445, 1340 cm ; H NMR (400 MHz) δ
.88−2.81 (m, 1H), 1.90−1.85 (m, 3H), 1.76−1.73 (m, 1H), 1.68−1.58
−1 1
1
7
1
1
445, 1274 cm ; H NMR (400 MHz) δ 7.70−7.67 (m, 2H), 7.62−
2
13
.54 (m, 4H), 6.78−6.74 (m, 1H), 3.81 (s, 3H); C NMR (100 MHz) δ
70.5, 166.7, 152.7, 131.5, 130.1, 129.3 (2C), 127.9 (2C), 126.2, 121.5,
09.8, 51.9; HRMS (ESI-TOF) (m/z): calcd for C H ClNO , [M −
H] 262.0276; found 262.0272. Anal. Calcd for C H ClNO : C,
13
(
5
m, 2H), 1.43−1.26 (m, 4H); C NMR (100 MHz) δ 178.9, 157.0,
7.9, 37.9, 29.8 (2C), 25.8 (2C), 25.5; HRMS (ESI-TOF) (m/z): calcd
+
13 10
3
for C H ClINO, [M + H] 311.9647; found 311.9652.
−
9
11
13
10
3
3
-Chloro-4-iodo-5-cyclopentyl-isoxazole (1o). Yellowish oil
5
9.22; H, 3.82; N, 5.31. Found: C, 59.04; H, 3.94; N, 5.50.
Synthesis of 3-Chloro-4-[(4-methoxyphenyl)ethynyl]-5-
−1 1
(
(
4
3
115 mg, 77%). IR (KBr) ν 2960, 2872, 1571, 1344 cm ; H NMR
400 MHz) δ 3.30−3.22 (m, 1H), 2.06−2.02 (m, 2H), 1.86−1.79 (m,
H), 1.71−1.70 (m, 2H); C NMR (100 MHz) δ 178.8, 157.1, 58.6,
6f
phenylisoxazole (8). After the mixture of 1a (153 mg, 0.5 mmol),
13
1
-ethynyl-4-methoxybenzene (132 mg, 1 mmol), n-Bu NBr (161 mg,
4
8.3, 31.0 (2C), 25.7 (2C). HRMS (ESI-TOF) (m/z): calcd for
0
.5 mmol), K CO (166 mg, 1.2 mmol), and Pd(PPh ) Cl (7 mg, 0.01
+
2
3
3
2
2
C H ClINO, [M + H] 297.9490; found 297.9489.
8
9
mmol) in DMF (2 mL) in a Schlenk tube was degassed, it was stirred for
6 h at 60 °C under N . Then the resultant mixture was poured into H O
3
-Chloro-4-iodo-5-cyclopropyl-isoxazole (1p). Colorless oil
1
−1
1
2
2
(
109 mg, 81%). IR (KBr) ν 2925, 1581, 1340 cm ; H NMR (400
(
15 mL) and was extracted with CH Cl (3 × 15 mL). The combined
13
2 2
MHz) δ 2.10−2.03 (m, 1H), 1.21−1.11 (m, 4H); C NMR (100 MHz)
δ 176.0, 157.2, 58.2, 9.4, 8.7 (2C). HRMS (ESI-TOF) (m/z): calcd for
organic layers were washed with brine (15 mL) and dried over Na SO .
2
4
+
The solvent was removed on a rotavapor, and the residue was purified by
flash chromatography [silica gel, 5% EtOAc in petroleum ether (60−90
°C)] to give 128 mg (83%) of 8 as a white solid, mp 103−105 °C. IR ν
C H ClINO, [M + H] 269.9177; found 269.9181.
6
5
3
-Chloro-4-iodo-5-(tert-butoxymethyl)isoxazole (1q). Color-
−1 1
less oil (147 mg, 93%). IR ν 2976, 1584, 1339 cm ; H NMR (400
−1 1
13
2973, 2221, 1603, 1510, 1403, 1276, 1249 cm ; H NMR (400 MHz) δ
.17−8.15 (m, 2H), 7.52−7.51 (m, 5H), 6.92 (d, J = 8.7 Hz, 2H), 3.84
MHz) δ 4.53 (s, 2H), 1.29 (s, 9H); C NMR (100 MHz) δ 172.3, 157.4,
5.1, 61.1, 55.9, 27.3 (3C); HRMS (ESI-TOF) (m/z): calcd for
8
7
13
+
(s, 3H); C NMR (100 MHz) δ 169.5, 160.3, 155.3, 133.2 (2C), 131.3,
29.0 (2C), 126.6, 126.1 (2C), 114.2 (2C), 114.1, 99.6, 97.7, 74.9, 55.3;
C H ClINO , [M + H] 315.9596; found 315.9588.
8
11
2
1
2
-(3-Chloro-4-iodo-isoxazol-5-yl)-ethan-1-ol (1r). Yellowish oil
+
−1 1
HRMS (ESI-TOF) (m/z): calcd for C H ClNO , [M + H] 310.0629;
(
105 mg, 77%). IR ν 3416, 2889, 1579, 1433, 1345 cm ; H NMR (400
18 12 2
found 310.0631. Anal. Calcd for C H ClNO : C, 69.80; H, 3.90; N,
MHz) δ 3.99 (t, J = 6.0 Hz, 2H), 3.09 (t, J = 6.4 Hz, 2H), 1.96 (s, 1H);
18 12
2
1
3
4.52. Found: C, 69.51; H, 3.91; N, 4.59.
C NMR (100 MHz) δ 173.6, 157.4, 61.2, 59.5, 31.1; HRMS (ESI-
+
TOF) (m/z): calcd for C H ClINO , [M + H] 273.9126; found
5
5
2
2
73.9124.
Ethyl 3-Chloro-4-iodoisoxazole-5-carboxylate (1s). White
solid (115 mg, 76%), mp 109−110 °C. IR ν 2992, 1724, 1442, 1258
ASSOCIATED CONTENT
■
*
S
Supporting Information
−1
1
1
13
cm ; H NMR (400 MHz) δ 4.48 (q, J = 7.4 Hz, 2H), 1.45 (t, J = 7.4 Hz,
H and C NMR spectra for products 1a−1t, as well as a CIF file
3
H); 13C NMR (100 MHz) δ 160.9, 159.4, 155.5, 68.2, 63.0, 14.0;
for the single crystal X-ray diffraction analysis of 1a. This material
+
HRMS (ESI-TOF) (m/z): calcd for C H ClINO , [M + H] 301.9075;
6
5
3
is available free of charge via the Internet at http://pubs.acs.org.
found 301.9072. Anal. Calcd for C H ClINO : C, 23.90; H, 1.67; N,
6
5
3
4
.65. Found: C, 23.89; H, 1.76; N, 4.71.
,3′-Dichloro-4′-iodo-5-methyl-4,5-dihydro-5,5′-biisoxazole
1t). Yellowish oil (69 mg, 40%). IR ν 2988, 1569, 1432, 1330, 1131
AUTHOR INFORMATION
3
■
*
(
−
1
1
Corresponding Authors
E-mail: wangxinyan@mail.tsinghua.edu.cn.
*E-mail: yfh@mail.tsinghua.edu.cn.
cm ; H NMR (400 MHz) δ 3.72 (d, J = 17.9 Hz, 1H), 3.28 (d, J = 17.4
13
Hz, 1H), 1.92 (s, 3H); C NMR (100 MHz) δ 171.7, 159.0, 148.1, 84.4,
59.1, 49.2, 24.6; HRMS (ESI-TOF) (m/z): calcd for C H Cl IN O , [M
7
5
2
2
2
+
+
H] 346.8846; found 346.8857. Anal. Calcd for C H Cl IN O : C,
7 5 2 2 2
Notes
24.23; H, 1.45; N, 8.07. Found: C, 24.10; H, 1.53; N, 8.19.
The authors declare no competing financial interest.
Synthesis of 3-Chloro-4-(3-nitrophenyl)-5-phenyl-isoxazole
7
d
(6). After the mixture of 1a (153 mg, 0.5 mmol), 3-nitrophenyl-
boronic acid (117 mg, 0.7 mmol), KHCO (70 mg, 0.7 mmol), and
3
ACKNOWLEDGMENTS
■
PdCl (5 mg, 0.025 mmol) in DMF−H O (4:1, 3 mL) in a Schlenk tube
2
2
was degassed, it was stirred for 24 h at 80 °C under N . Then the
This work was supported by NNSFC (Nos. 21472107,
21372142, and 21221062).
2
resultant mixture was poured into H O (15 mL) and was extracted with
2
D
DOI: 10.1021/jo502634h
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
́
1
1
49−152. (h) García-Alverez, J.; Díez, J.; Gimeno, J. Green Chem. 2010,
2, 2127−2130. (i) Hein, J. E.; Tripp, J. C.; Krasnova, L. B.; Sharpless, K.
REFERENCES
■
(
1) For reviews, see: (a) Kumar, K. A.; Jayaroopa, P. Int. J. Pharm.
B.; Fokin, V. V. Angew. Chem., Int. Ed. 2009, 48, 8018−8021.
11) For example, the mixture of 1-iodoalkyne, azide, and CuI failed to
Chem. Biol. Sci. 2013, 3, 294−304. (b) Giomi, D.; Cordero, F. M.;
Machetti, F. Isoxazoles. In Comprehensive Heterocyclic Chemistry III;
Katritzky, A. R., Ramsden, C. A., Scriven, E. F. V., Taylor, R. J. K., Eds.;
Elsevier: Oxford, 2008; Vol. 4, pp 365−486. (c) Pinho e Melo, T. M. V.
D. Curr. Org. Chem. 2005, 9, 925−958. (d) Grunanger, P.; Vita Finzi, P.
Isoxazole. Part I; In The Chemistry of Heterocyclic Compounds; Taylor, E.
C., Weissberger, A., Eds.; Wiley: New York, 1990; pp 183−209.
(
give a cycloaddition product; see: Kuijpers, B. H. M.; Dijkmans, G. C. T.;
Groothuys, S.; Quaedflieg, P. J. L. M.; Blaauw, R. H.; van Delft, F. L.;
Rutjes, F. P. J. T. Synlett 2005, 3059−3062. Yet the same mixture gave
excellent yields of 5-iodo-1,2,3-triazoles in the presence of a ligand; see
ref 10i.
(
12) (a) Nouzarian, M.; Hosseinzadeh, R.; Golchoubian, H. Synth.
(
1
(
(
2) De Amici, M.; De Micheli, C.; Carrea, G.; Spezia, S. J. Org. Chem.
Commun. 2013, 43, 2913−2925. (b) Starkov, P.; Rota, F.; D’Oyley, J.
989, 54, 2646−2650.
M.; Sheppard, T. D. Adv. Synth. Catal. 2012, 354, 3217−3224.
3) Waldo, J. P.; Larock, R. C. J. Org. Chem. 2007, 72, 9643−9647.
(
c) Reddy, K. R.; Venkateshwar, M.; Maheswari, C. U.; Kumar, P. S.
4) For selected references: (a) Liu, Y.; Cui, Z.; Liu, B.; Cai, B.; Li, Y.;
Tetrahedron Lett. 2010, 51, 2170−2173. (d) Yan, J.; Li, J.; Cheng, D.
Synlett 2007, 2442−2444. (e) Kabalka, G. W.; Mereddy, A. R.
Tetrahedron Lett. 2004, 45, 1417−1419. (f) Homsi, F.; Rousseau, G.
Tetrahedron Lett. 1999, 40, 1495−1498. (g) Monenschein, H.;
Soukourni-Argirusi, G.; Schubothe, K. M.; O’Hare, T.; Kirschning, A.
Org. Lett. 1999, 1, 2101−2104. (h) Naskar, D.; Roy, S. J. Org. Chem.
Wang, Q. J. Agric. Food Chem. 2010, 58, 2685−2689. (b) Dallanoce, C.;
Frigerio, F.; De Amici, M.; Dorsch, S.; Klotz, K.-N.; De Micheli, C.
Bioorg. Med. Chem. 2007, 15, 2533−2543. (c) Cha, J. H.; Cho, Y. S.; Pae,
A. N.; Koh, H. Y.; Jeong, D.; Kong, J. Y.; Lee, E.; Choi, K. I. Bioorg. Med.
Chem. Lett. 2001, 11, 2855−2857. (d) Kim, D. J.; Seo, K. J.; Lee, K. S.;
Shin, K. J.; Yoo, K. H.; Kim, D. C.; Park, S. W. Bioorg. Med. Chem. Lett.
1
1
9
(
2
999, 64, 6896−6897. (i) Brunel, Y.; Rousseau, G. Tetrahedron Lett.
995, 36, 2619−2622. (j) Jeffery, T. J. Chem. Soc., Chem. Commun. 1988,
09−910.
2
000, 10, 2799−2802. (e) Chiarino, D.; Grancini, G.; Frigeni, V.;
Biasini, I.; Carenzi, A. J. Med. Chem. 1991, 34, 600−605. (f) Wigerinck,
P.; Snoeck, R.; Claes, P.; De Clercq, E.; Herdewijn, P. J. Med. Chem.
13) Pelletier, G.; Lie, S.; Mousseau, J. J.; Charette, A. B. Org. Lett.
1
991, 34, 1767−1772. (g) Franke, A.; Frickel, F.-F.; Gries, J.; Lenke, D.;
Schlecker, R.; Thieme, P. D. J. Med. Chem. 1981, 24, 1460−1464.
h) Carr, J. B.; Durham, H. G.; Hass, D. K. J. Med. Chem. 1977, 20, 934−
39.
5) (a) Moore, J. E.; Davies, M. W.; Goodenough, K. M.; Wybrow, R.
A. J.; York, M.; Johnson, C. N.; Harrity, J. P. A. Tetrahedron 2005, 61,
012, 14, 5464−5467. In this article, the decomposition of 1-
iodoalkynes was studied and a special note was given in the SI (pp
S12−S13): “Note: The synthesized 1-iodoalkynes were found usually
unstable to light exposure and trace of iodine is observed when the
product is solubilized or purified by flash chromatography (a pink color
gradually appears when flashed or stored on the bench at room
temperature). They should be kept under argon in the freezer (−20 °C)
or use directly in a further reaction.”
(
9
(
6
707−6714. (b) Stevens, J. L.; Welton, T. D.; Deville, J. P.; Behar, V.
Tetrahedron Lett. 2003, 44, 8901−8903. (c) Ruano, J. L. G.; Fraile, A.;
Martin, M. R. Tetrahedron 1999, 55, 14491−14500. (d) Chiarino, D.;
Napoletano, M.; Sala, A. J. Heterocycl. Chem. 1987, 24, 43−46.
(
14) Wang, B.; Zhang, J.; Wang, X.; Liu, N.; Chen, W.; Hu, Y. J. Org.
Chem. 2013, 78, 10519−10523.
15) (a) Woon, E. C. Y.; Dhami, A.; Mahon, M. F.; Threadgill, M. D.
(
6) (a) Choi, M. J.; No, E. S.; Thorat, D. A.; Jang, J. W.; Yang, H.; Lee,
(
J.; Choo, H.; Kim, S. J.; Lee, C. S.; Ko, S. Y.; Lee, J.; Nam, G.; Pae, A. N. J.
Med. Chem. 2013, 56, 9008−9018. (b) Wang, X.-C.; Hu, Y.; Bonacorsi,
S.; Hong, Y.; Burrell, R.; Yu, J. Q. J. Am. Chem. Soc. 2013, 135, 10326−
Tetrahedron 2006, 62, 4829−4837. (b) Owsley, D. C.; Castro, C. E. Org.
Synth. 1972, 52, 128−130. (c) Castro, C. E.; Havlin, R.; Honwad, V. K.;
Malte, A.; Moje, S. J. Am. Chem. Soc. 1969, 91, 6464−6470. (d) Stephens,
R. D.; Castro, C. E. J. Org. Chem. 1963, 28, 3313−3315.
1
2
0329. (c) Iglesias, M.; Schuster, O.; Albrecht, M. Tetrahedron Lett.
010, 51, 5423−5425. (d) Brough, P. A.; Aherne, W.; Barril, X.;
(
16) Recent works on 1-Cu(I) alkynes: (a) Jouvin, K.; Veillard, R.;
Borgognoni, J.; Boxall, K.; Cansfield, J. E.; Cheung, K.-M. J.; Collins, I.;
Davies, N. G. M.; Drysdale, M. J.; Dymock, B.; Jordan, A. M.; Lockie, A.;
Martins, V.; Massey, A.; Matthews, T.; McDonald, E.; Northfield, C. J.;
Pearl, L. H.; Prodromou, C.; Ray, S.; Raynaud, F. I.; Roughley, S. D.;
Sharp, S. Y.; Surgenor, A.; Walmsley, D. L.; Webb, P.; Wood, M.;
Workman, P.; Wright, L. J. Med. Chem. 2008, 51, 196−218. (e) Day, R.
A.; Blake, J. A.; Stephens, C. E. Synthesis 2003, 1586−1590. (f) Kromann,
H.; Sløk, F. A.; Johansen, T. N.; Krogsgaard-Larsen, P. Tetrahedron
Theunissen, C.; Alayrac, C.; Gaumont, A.-C.; Evano, G. Org. Lett. 2013,
1
5, 4592−4595. (b) Verna, F.; Guissart, C.; Pous, J.; Evano, G. Monatsh.
Chem. 2013, 144, 523−529. (c) Laouiti, A.; Jouvin, K.; Bourdreux, F.;
Rammah, M. M.; Rammah, M. B.; Evano, G. Synthesis 2012, 44, 1491−
1
7
500. (d) Jouvin, K.; Heimburger, J.; Evano, G. Chem. Sci. 2012, 3, 756−
60. (e) Buckley, B. R.; Dann, S. E.; Heaney, H.; Stubbs, E. C. Eur. J. Org.
Chem. 2011, 770−776.
17) For our recent works on 1-Cu(I) alkynes, see: Reference 14 and
a) Chen, W.; Wang, B.; Liu, N.; Huang, D.; Wang, X.; Hu, Y. Org. Lett.
014, 16, 6140−6143. (b) Wang, B.; Liu, N.; Chen, W.; Huang, D.;
(
(
2
2
(
001, 57, 2195−2201.
7) (a) kalin, J. H.; Zhang, H.; Gaudrel-Grosay, S.; Vistoli, G.;
Kozikowski, A. P. ChemMedChem 2012, 7, 425−439. (b) Okitsu, T.;
Wang, X.; Hu, Y. Adv. Synth. Catal. 2014, 356, ASAP (DOI: 10.1002/
adsc.201400471). (c) Wang, B.; Ahmed, M. N.; Zhang, J.; Chen, W.;
Wang, X.; Hu, Y. Tetrahedron Lett. 2013, 54, 6097−6100. (d) Wang, B.;
Liu, N.; Shao, C.; Zhang, Q.; Wang, X.; Hu, Y. Adv. Synth. Catal. 2013,
Sato, K.; Potewar, T. M.; Wada, A. J. Org. Chem. 2011, 76, 3438−3449.
(
c) Debleds, O.; Gayon, E.; Ostaszuk, E.; Vrancken, E.; Campagne, J.-M.
Chem.Eur. J. 2010, 16, 12207−12213. (d) Waldo, J. P.; Mehta, S.;
Neuenswander, B.; Lushington, G. H.; Larock, R. C. J. Comb. Chem.
3
55, 2564−2568.
2008, 10, 658−663. (e) Waldo, J. P.; Larock, R. C. J. Org. Chem. 2007,
72, 9643−9647. (f) Waldo, J. P.; Larock, R. C. Org. Lett. 2005, 7, 5203−
5205.
(
8) (a) Oakdale, J. S.; Sit, R. K.; Fokin, V. V. Chem.Eur. J. 2014, 20,
1
2
2
1101−11110. (b) Jackowshi, O.; Lecourt, T.; Micouin, L. Org. Lett.
011, 13, 5664−5667. (c) Crossley, J. A.; Browne, D. L. J. Org. Chem.
010, 75, 5414−5416.
(
9) Grundmann, C. Synthesis 1970, 344−359.
́
10) (a) Lal, S.; Rzepa, H. S.; Díez-Gonzalez, S. ACS Catal. 2014, 4,
(
2
3
1
7
274−2287. (b) Worrell, B. T.; Malik, J. A.; Fokin, V. V. Science 2013,
40, 457−460. (c) Fu, D.; Zhang, J.; Cao, S. J. Fluorine Chem. 2013, 156,
70−176. (d) Brotherton, W. S.; Clark, R. J.; Zhu, L. J. Org. Chem. 2012,
́
7, 6443−6455. (e) García-Alverez, J.; Díez, J.; Gimeno, J.; Suar
́
ez, F. J.;
k, M.; Stout,
Vincent, C. E. J. Inorg. Chem. 2012, 5854−5863. (f) Juríce
̌
K.; Kouwer, P. H.; Rowan, A. E. Org. Lett. 2011, 13, 3494−3497.
(
g) Recsei, C.; McErlean, C. S. P. Tetrahedron: Asymmetry 2010, 21,
E
DOI: 10.1021/jo502634h
J. Org. Chem. XXXX, XXX, XXX−XXX