1742
J. J. Letourneau et al. / Tetrahedron Letters 48 (2007) 1739–1743
9. (a) Christl, M.; Huisgen, R. Chem. Ber. 1973, 106, 3345;
(b) Shankar, B. B.; Yang, D. Y.; Girton, S.; Ganguly, A.
K. Tetrahedron Lett. 1998, 39, 2447–2448.
10. Torsell, K. G. B. Nitrile Oxides, Nitrones and Nitronates in
Organic Synthesis; VCH: New York, 1988.
2-aryl-1-bromoalkyne as the key step. In addition, we
have demonstrated the utility of these 5-aryl-4-bromo-
3-carboxyisoxazoles for the solid-phase synthesis of
4,5-diarylisoxazoles.
11. Mukaiyama, T.; Hoshino, T. J. Am. Chem. Soc. 1960, 82,
5339.
12. 2-(2-Nitroethoxy)tetrahydropyran is commercially avail-
able from Aldrich and TCI america. It is also easily
obtained from THP protection of 2-nitroethanol, see:
Kozikowski, A. P.; Adamcz, M. J. Org. Chem. 1983, 48,
366–372.
13. Regiochemical assignment of isoxazole products is made
on the basis of diagnostic 13C resonances using NMR data
for compound 8g and its derivative 10g; the signals for C-4
of the isoxazole ring at 89.6 ppm in the 13C NMR of 8g
(see Ref. 15 for spectral data for 8g) and at 89.1 ppm in the
13C NMR of 10g (see Ref. 19 for spectral data for 10g) are
consistent with Br-substitution at C-4 of the isoxazole
ring. For representative 13C NMR data of some 5-aryl-4-
bromo isoxazoles, see: Day, R. A.; Blake, J. A.; Stephens,
C. E. Synthesis 2003, 1586–1590.
References and notes
1. (a) Rowley, M.; Broughton, H. B.; Collins, I.; Baker, R.;
Emms, F.; Marwood, R.; Patel, S.; Patel, S.; Ragan, C. I.;
Freedman, S. B.; Leeson, P. D. J. Med. Chem. 1996, 39,
1943–1945; (b) Simoni, D.; Invidiata, F. P.; Rondanin, R.;
Grimaudo, S.; Cannizzo, G.; Barbusca, E.; Porretto, F.;
D’Alessandro, N.; Tolomeo, M. J. Med. Chem. 1999, 42,
4961–4969; (c) Maloney, P. R.; Parks, D. J.; Haffner, C.
D.; Fivush, A. M.; Gyan, C.; Plunket, K. D.; Creech, K.
L.; Moore, L. B.; Wilson, J. G.; Lewis, M. C.; Jones, S. A.;
Willson, T. M. J. Med. Chem. 2000, 43, 2971–2974; (d)
Simoni, D.; Roberti, M.; Invidiata, F. P.; Rondanin, R.;
Baruchello, R.; Malagutti, C.; Mazzali, A.; Rossi, M.;
Gimaudo, S.; Capone, F.; Dusonchet, L.; Meli, M.;
Raimondi, M. V.; Landino, M.; D’Allessandro, N.;
Tolomeo, M.; Arindam, D.; Lu, S.; Benbrook, D. M. J.
Med. Chem. 2001, 44, 2308–2318; (e) Habeeb, A. G.; Rao,
P. N. P.; Knaus, E. E. J. Med. Chem. 2001, 44, 2921–2927;
(f) Talley, J. J.; Bertenshaw, S. R.; Brown, D. L.; Carter, J.
S.; Graneto, M. J.; Kellogg, M. S.; Koboldt, C. M.; Yuan,
J.; Zhang, Y. Y.; Seibert, K. J. Med. Chem. 2000, 43,
1661–1663; (g) Talley, J. J.; Brown, D. L.; Carter, J. S.;
Graneto, M. J.; Koboldt, C. M.; Masferrer, J. L.; Perkins,
W. E.; Rogers, R. S.; Shaffer, A. F.; Zhang, Y. Y.; Zweifel,
B. S.; Seibert, K. J. Med. Chem. 2000, 43, 775–777; (h)
Habeeb, A. G.; Rao, P. N. P.; Knaus, E. E. Drug Dev. Res.
2000, 51, 273–286; (i) Haslam, E. Shikimic Acid Meta-
bolism and Metabolites; John Wiley & Sons: New York,
1993.
14. For the use of slow syringe pump addition of a nitroalkane
to minimize dimerization of an in situ generated nitrile
oxide, see: Evans, D. A.; Ripin, D. H. B.; Halstead, D. P.;
Campos, K. R. J. Am. Chem. Soc. 1999, 121, 6816–
6826.
1
15. All new isoxazoles 8c–m gave satisfactory H NMR and
mass spectroscopy data. Compound 8g was fully charac-
terized (see data below). A typical experimental procedure
is exemplified by the synthesis of 8g: To a solution of
1-bromoethynyl-4-methylbenzene (9.10 g; 46.65 mmol),
phenylisocyanate (9.89 g; 90.97 mmol), and DIPEA
(8.13 mL; 46.65 mmol) in toluene (150 mL) at 90 ꢂC was
added
2-(2-nitroethoxy)tetrahydropyran
(7.15 mL;
46.65 mmol) as a solution in toluene (10 mL) via syringe
pump over a period of 16 h. After complete addition of the
nitro alkane, the reaction mixture was stirred for an
additional 2 h. The reaction mixture was cooled, filtered
through a plug of Celite to remove the diphenylurea by-
product and concentrated in vacuo. The crude residue was
purified by silica gel chromatography (elution with 8:1
hexanes/EtOAc) providing 3.94 g of isoxazole 8g (24%)
and 5.40 g of recovered 1-bromoethynyl-4-methylbenzene
(83% b.o.r.s.m.); data for 8g: 1H NMR (CDCl3,
300 MHz): d 7.92 (2H, d, 8.0 Hz, Ar–H), 7.30 (2H, d,
8.0 Hz, Ar–H), 4.85 (1H, t, 3.0 Hz) 4.72 (2H, ABq,
12.4 Hz, DmAB = 64.5 Hz, CH2OTHP), 3.97 (1H, ddd,
11.5, 9.2, 3.0 Hz), 3.60 (1H, dtd, 11.3, 4.1, 1.7 Hz), 2.41
(3H, s), 1.94–1.50 (6H, m); 13C NMR (CDCl3, 75 MHz): d
165.5, 160.8, 141.2, 129.6, 126.8, 123.9, 98.5, 98.4, 89.6,
62.0, 59.6, 59.5, 30.3, 25.5, 21.7, 18.9; MS (ESI): m/z
(% relative intensity, assignment) 268.0 + 270.0 (100,
[M+HꢀTHP]+); Anal. Calcd for C16H18BrNO3: C,
54.56; H, 5.15; N, 3.98. Found: C, 54.39; H, 4.97; N, 3.99.
16. Greene, T. W.; Wuts, P. G. M. Protective Groups in
Organic Synthesis; John Wiley and Sons: New York, 1991,
and references cited therein.
2. (a) Baldwin, J. J.; Burbaum, J. J.; Henderson, I.;
Ohlmeyer, M. H. J. J. Am. Chem. Soc. 1995, 117, 5588–
5589; (b) Ohlmeyer, M. H. J.; Swanson, R. N.; Dillard, L.
W.; Reader, J. C.; Asouline, G.; Kobayashi, R.; Wigler,
M.; Still, W. C. Proc. Natl. Acad. Sci. USA 1993, 90,
10922–10926; (c) Nestler, H. P.; Bartlett, P. A.; Still, W. C.
J. Org. Chem. 1994, 59, 4723–4724.
3. The R1 amine, the isoxazole scaffold (providing R2) and
the R3 boronic acid can each be varied to provide a
combinatorial diversity.
4. (a) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457–
2483; (b) Suzuki, A. Pure Appl. Chem. 1994, 66, 213; (c)
Miyaura, N.; Yanagi, T.; Suzuki, A. Synth. Commun.
1981, 11, 513–519.
5. To the best of our knowledge, there is only a single
example reported in the literature on the use of an
arylhaloalkyne in such a cycloaddition to give a 5-aryl-4-
haloisoxazole. In this example, 1-phenyl-2-iodoethyne was
reacted with mesitonitrile oxide providing the correspond-
ing isoxazole in 83% yield as a single regioisomer: Kotali,
E.; Varvoglis, A.; Bozopoulos, A. J. Chem. Soc., Perkin
Trans. 1 1989, 827–832.
6. For examples of 1,3-dipolar cycloadditions of alkynyl
iodonium salts with nitrile N-oxides, see: Ref. 5 and
Kitamura, T.; Mansei, Y.; Fujiwara, Y. J. Organomet.
Chem. 2002, 196–199.
17. Parikh, J. R.; Doering, W. E. J. Am. Chem. Soc. 1967, 89,
5507.
18. The pyridyl containing isoxazole 9e was oxidized to the
aldehyde with the Dess-Martin periodinane instead of
pyridine*SO3 complex. The methylthio substituent in 8k
was oxidized to a sulfonyl group with 2 equiv of m-CPBA
prior to THP deprotection and subsequent oxidation to
the carboxylic acid.
19. Typical experimental procedure as exemplified by the
synthesis of acid 10g: To a solution of THP ether 8g
(4.12 g; 11.70 mmol) in MeOH (50 mL) was added 132 mg
7. Corey, E. J.; Fuchs, P. L. Tetrahedron Lett. 1972, 3769–
3772.
8. Ratovelomanana, V.; Rollin, Y.; Gebehenne, C.; Gosmini,
C.; Perichon, J. Tetrahedron Lett. 1994, 35, 4777–4780.