isoxazoles and their derivatives.7 In connection with our
studies on the synthesis of pyridyl isoxazole derivatives 3,
it was envisioned that the 3-pyridyl 5-substituted isoxazole
derivatives 3 would arise from the Pd-catalyzed coupling
reactions of 2-(5-iodoisoxazol-3-yl)pyridine 2 with various
organometallic substances to generate structurally diverse
5-substituted isoxazoles (Scheme 1).
Scheme 3
Regarding the stability of iodoacetylene 1, thermal stability
studies were conducted using a differential scanning calo-
rimeter (DSC) and an accelerating rate calorimeter (ARC).
The studies indicated that a 0.5 M solution of iodoacetylene
1 in THF was stable up to 160 °C (DSC). An exotherm
started at 160 °C and ended at 188 °C, evolving 57.4 J/g.
The exothermic event was not sufficiently large to raise
concern, and the THF solution of iodoacetylene 1 was stable
under the normal conditions. The THF solution can be used
directly in the [2 + 3] cycloaddition reaction with the 1,3-
dipolar nitrile oxide to produce the desired 2-(5-iodoisoxazol-
3-yl)pyridine 212 in high yield (90%). Notably, the reaction
is completely regioselective. The regioisomer, 4-iodoisox-
azole, was not detected by HPLC.
Alternatively, iodoacetylene 1 can also be prepared in situ
by reacting ethynylmagnesium bromide 6 with iodine in THF
(Scheme 3). This procedure produced lower quality io-
doacetylene 1. Subsequently, the 2-(5-iodoisoxazol-3-yl)-
pyridine 2 was prepared in lower yield (50%).13
By a different procedure, the iodoacetylene 1 generated
from reacting iodine with tributyl(ethynyl)tin 5 in THF was
further purified by co-distilling with THF at 70 °C under
atmospheric pressure. The benefit of using this distilled THF
Scheme 1
Generally, isoxazoles are constructed by [2 + 3] cycload-
dition of a nitrile oxide to an alkyne,8 with the 1,3-dipolar
intermediate generated in situ from the corresponding hy-
droximoyl chloride9 or primary nitro compound.10 There are
only a few reports for the preparation of 5-haloisoxazoles.7,11
5-Bromo- and 5-chloroisoxazole derivatives were synthesized
by the reactions of halogenated cyclopropanes with nitrosyl
cation.7d 5-Chloroisoxazoles were prepared by the cyclo-
addition of nitrile oxides to 1,1-dichloroethylene,11a and
iodoisoxazole was prepared by iodination of the correspond-
ing 5-(tributylstannyl)isoxazole.11b
We would like to report here a direct approach to
5-iodoisoxazole derivatives. The synthesis of 2 involves the
[2 + 3] cycloaddition of 2-pyridyl nitrile oxide generated in
situ from the corresponding 2-pyridyl oxime chloride 4 with
iodoacetylene 1 as a dipolarphile (Scheme 2). The iodoacety-
(8) (a) Kozikowski, A. P. Acc. Chem. Res. 1984, 17, 410-416. (b)
Caramella, P.; Grunanger, P. 1,3-Dipolar Cycloaddition Chemistry; Padwa,
A., Ed.; Wiley: New York, 1984.
(9) Christl, M.; Huisgen, R. Chem. Ber. 1973, 106, 3345-3367.
(10) Mukaiyama, T.; Hoshino, T. J. Am. Chem. Soc. 1960, 82, 5339-
5342.
(11) (a) Stevens, R. V.; Albizati, K. F. Tetrahedron Lett. 1984, 25, 4587
(b) Sakamoto, T.; Kondo, Y.; Uchiyama, D.; Yamanaka, H. Tetrahedron
1991, 47, 5111.
Scheme 2
(12) Typical procedure: To a cooled (0 °C) solution of tributyl(ethynyl)-
tin 5 (11.6 mL, 40 mmol) in THF (20 mL) was added iodine (11.1 g, 43
mmol) portionwise keeping the temperature below 10 °C. The mixture was
stirred at 0 °C until the iodine color persist (∼10 min). To the above solution
was added the pyridyl oxime chloride 4 (prepared from the reaction of the
corresponding oxime with chlorine gas, 962 mg, 5 mmol) followed by
dropwise addition of a solution of Et3N (1.6 mL, 11 mmol) in THF (5 mL)
over a period of 5 min. The reaction mixture was stirred at 0 °C for 15 min
and then allowed to warm to room temperature and stirred until all the
chloro-oxime was consumed (∼1 h, monitored by HPLC, HPLC assay yield
is 90%). To the reaction mixture were added ethyl acetate and 10% sodium
thiosulfate. The organic layer was separated, dried over Na2SO4, and
concentrated to an oil. The product was purified by being passed through
a pad of silica gel to obtain 2-(5′-iodoisoxazol-3-yl)pyridine 2 in high purity
(99.5% peak area) in 75% isolated yield. The X-ray structure of 2 was
obtained: mp 105 °C. Anal. Calcd for C8H5IN2O: C, 35.32; H, 1.85; I,
46.65; N, 10.30. Found: C, 35.27; H, 1.92; I, 46.40; N, 10.19. 1H NMR
(CDCl3) δ 7.12 (1H, s), 7.37 (1H, m), 7.80 (1H, m), 8.04 (1H, m) and 8.69
(1H, m); 13CMR (CDCl3) δ 110.6, 113.6, 121.6, 124.8, 136.9, 147.3, 149.8
and 164.5. DCIMS: m/z 273 (M+ + 1), 290 (M+ + NH4). HRMS: requires
272.9525, found 272.9516.
lene 1 was prepared efficiently by reacting iodine with
tributyl(ethynyl)tin 5 in THF (Scheme 3). Its formation was
confirmed by GC-MS and NMR analysis.
(7) (a) Lautens, M.; Roy, A. Org. Lett. 2000, 2, 555. (b) Martins, M. A.
P.; Flores, A. F. C.; Bastos, G. P.; Sinhorin, A.; Bonacorso, H. G.; Zanatta,
N. Tetrahedron Lett. 2000, 41, 293. (c) Sammelson, R. E.; Miller, R. B.;
Kurth, M. J. J. Org. Chem. 2000, 65, 2225. (d) Falorni, M.; Giacomelli,
G.; Spanu, E. Tetrahedron Lett. 1998, 39, 9241. (e) Lin, S. T.; Kuo, S. H.;
Yang, F. M. J. Org. Chem. 1997, 62, 5229. (f) Kantorowski, E. J.; Kurth,
M. J. J. Org. Chem. 1997, 62, 6797. (g) Lin, S. T.; Lin, L. H.; Yao, Y. F.
Tetrahedron Lett. 1992, 3155. (h) Lin, S. T.; Yang, Y. M. J. Chem. Res.
Synop. 1996, 276; J. Chem. Res. Miniprint 1996, 1554.
(13) When ethynylmagnesium bromide 6 was used in the place of
tributyl(ethynyl)tin for the preparation of 1, longer stirring time (∼2 h)
and higher temperatures were used after the addition of iodine. Water (∼1
mL) was added to the reaction mixture to destroy any unreacted Grignard
reagent before the pyridinyl oxime chloride was added. K2CO3 was used
instead of Et3N.
4186
Org. Lett., Vol. 3, No. 26, 2001